Existing Annotations Review

Core Functions

LRRK2 contains a kinase domain that phosphorylates Rab GTPases at threonine residues in their switch II regions. Primary substrates include Rab8A (Thr72), Rab10 (Thr73), Rab12 (Thr73), and Rab29 (Thr71).

Molecular Function:

protein serine/threonine kinase activity

The ROC (Ras of complex proteins) domain of LRRK2 binds and hydrolyzes GTP. GTP binding and hydrolysis regulate kinase domain activity through intramolecular signaling.

Molecular Function:

GTPase activity

LRRK2 ROC domain binds GTP, which is essential for regulating kinase activity. GTP binding status affects the conformation and enzymatic output of the protein.

Molecular Function:

GTP binding

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:16269541

Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.

PMID:16321986

The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.

PMID:16352719

Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.

PMID:16980962

Kinase activity of mutant LRRK2 mediates neuronal toxicity.

PMID:17114044

The familial Parkinsonism gene LRRK2 regulates neurite process morphology.

PMID:17120249

Localization of LRRK2 to membranous and vesicular structures in mammalian brain.

PMID:17200152

Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.

PMID:17260967

GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.

PMID:17400507

Identification of potential protein interactors of Lrrk2.

PMID:17442267

The R1441C mutation of LRRK2 disrupts GTP hydrolysis.

PMID:18230735

Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.

PMID:18367605

The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2.

PMID:18397888

The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.

PMID:18445495

LRRK2 regulates synaptic vesicle endocytosis.

PMID:19056867

Large-scale proteomics and phosphoproteomics of urinary exosomes.

PMID:19176810

The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.

PMID:19196961

CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity.

PMID:19302196

The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.

PMID:19559761

Interaction of elongation factor 1-alpha with leucine-rich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro.

PMID:19576176

Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.

PMID:19625296

Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.

PMID:19640926

LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.

PMID:19692353

Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.

PMID:19712061

Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.

PMID:19733152

The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.

PMID:20067578

MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2.

PMID:20144646

Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease.

PMID:20173330

LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.

PMID:20515039

Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation.

PMID:20642453

14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.

PMID:20659558

Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.

PMID:20671708

Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.

PMID:21048939

ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.

PMID:21073465

Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant.

PMID:21159966

LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.

PMID:21168496

Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.

PMID:21307259

LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.

PMID:21362567

LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.

PMID:21370995

Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.

PMID:21454543

Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2).

PMID:21563316

Synaptic vesicle trafficking and Parkinson's disease.

PMID:21658387

LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson's disease-associated mutations.

PMID:21696411

LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study.

PMID:21850687

Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.

PMID:21857923

Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans.

PMID:21983832

The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease.

PMID:22012985

Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.

PMID:22228096

LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.

PMID:22303461

LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.

PMID:22363216

GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.

PMID:22423108

ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2.

PMID:22612223

The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation.

PMID:22639965

Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein.

PMID:22664934

Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.

PMID:22736029

G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.

PMID:22764206

Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.

PMID:22899650

LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.

PMID:22952686

Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers.

PMID:22988876

The importance of Wnt signalling for neurodegeneration in Parkinson's disease.

PMID:22998870

LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.

PMID:23075850

Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.

PMID:23183827

LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models.

PMID:23220480

Dominant-negative effects of LRRK2 heterodimers: a possible mechanism of neurodegeneration in Parkinson's disease caused by LRRK2 I2020T mutation.

PMID:23241358

GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2.

PMID:23395371

RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.

PMID:23455607

Interplay of LRRK2 with chaperone-mediated autophagy.

PMID:23628791

Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.

PMID:23813973

Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation.

PMID:23916833

Inhibition of LRRK2 kinase activity stimulates macroautophagy.

PMID:23937259

Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle.

PMID:23949442

LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.

PMID:24113872

LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.

PMID:24115276

The regulation and deregulation of Wnt signaling by PARK genes in health and disease.

PMID:24165324

Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3β.

PMID:24211199

Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation.

PMID:24252804

The role of oxidative stress in Parkinson's disease.

PMID:24275654

A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.

PMID:24282027

Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily.

PMID:24351927

Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3.

PMID:24403142

Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies.

PMID:24459295

Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila.

PMID:24464040

LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.

PMID:24510904

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.

PMID:24576675

LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.

PMID:24591621

Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain.

PMID:24687852

Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.

PMID:24695735

The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.

PMID:24725412

Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.

PMID:24754922

MAP1B rescues LRRK2 mutant-mediated cytotoxicity.

PMID:24794857

A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.

PMID:24904275

LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex.

PMID:24947832

Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.

PMID:25009464

LRRK2 kinase activity and biology are not uniformly predicted by its autophosphorylation and cellular phosphorylation site status.

PMID:25201882

Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.

PMID:25360523

LRRK2 transport is regulated by its novel interacting partner Rab32.

PMID:25416817

Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.

PMID:25446991

Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy.

PMID:25500533

Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.

PMID:25501810

LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism.

PMID:25605758

An early endosome regulator, Rab5b, is an LRRK2 kinase substrate.

PMID:26014385

LRRK2 Promotes Tau Accumulation, Aggregation and Release.

PMID:26751287

The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.

PMID:26824392

Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.

PMID:26894577

Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2.

PMID:27013965

Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.

PMID:27273569

Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.

PMID:27314038

G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.

PMID:27357661

Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.

PMID:27424887

LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts.

PMID:27830463

LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation.

PMID:28202711

Structural interface between LRRK2 and 14-3-3 protein.

PMID:28720718

Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.

PMID:29513927

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.

PMID:29519959

P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity.

PMID:29541021

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1.

PMID:30398148

A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.

PMID:31046837

Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes.

PMID:31552791

LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.

PMID:32017888

Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33938021

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

PMID:38127736

Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.

PMID:38858457

Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

Reactome:R-HSA-8857565

Phosphorylated GPNMB recruits PTK6 and LRRK2 in the presence of LINC01139

Reactome:R-HSA-8857577

LINC01139 facilitates PTK6 autophosphorylation

Reactome:R-HSA-8857583

LINC01139 promotes phosphorylation of HIF1A by PTK6

Reactome:R-HSA-9634702

LINC01139 promotes phosphorylation of HIF1A by LRRK2

file:human/LRRK2/LRRK2-deep-research-falcon.md

Deep research report on LRRK2

📚 Additional Documentation

Deep Research Bioreason

(LRRK2-deep-research-bioreason.md)

BioReason Chat Export

Exported on March 22, 2026 at 01:40 AM

Organism: Homo sapiens

Sequence:

MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNIHVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILKMLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVEVLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQQYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWHRKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASANALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIMAAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKNDIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQEIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLARMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEGSFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLRSSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNV

Thinking Trace

I begin by dissecting the domain architecture. The N-terminal two-thirds of the protein are dominated by solenoidal repeat scaffolds: IPR011989 (Armadillo-like helical, residues 8–656) and IPR056597 (LRRK2, ARM repeat domain, residues 17–649) overlap with IPR016024 (Armadillo-type fold, residues 172–613). Immediately following, IPR036770 (Ankyrin repeat-containing domain superfamily, residues 657–803) and IPR056593 (LRRK2, ANK repeat domain, residues 679–808) extend this repeat-rich platform. These tandem ARM and ANK modules create an elongated, curved scaffold that specializes in multivalent protein–protein interactions and subcellular targeting. This N-terminal scaffold is followed by a C-terminal enzymatic core. Although the kinase region is late in the sequence, multiple signatures define it: IPR051420 (Ser/Thr Protein Kinases with Diverse Regulatory Roles, residues 766–2000) frames the regulatory kinase module; IPR000719 (Protein kinase domain, residues 1879–2000), IPR011009 (Protein kinase-like domain superfamily, residues 1884–2000), and IPR001245 (Serine-threonine/tyrosine-protein kinase, catalytic domain, residues 1885–2000) specify catalytic architecture, while IPR017441 (Protein kinase, ATP binding site, residues 1885–1906) marks the nucleotide-binding pocket that powers phosphorylation.

Inserted between the targeting scaffold and the kinase lies a composite GTPase engine: IPR020859 (Roc domain, residues 1328–1511) and IPR032171 (C-terminal of Roc, COR-A domain, residues 1545–1671) together with IPR057263 (C-terminal of Roc, COR-B domain, residues 1689–1858) form the Roc–COR tandem that couples nucleotide hydrolysis to conformational control. This GTPase module is reinforced by IPR027417 (P-loop containing nucleoside triphosphate hydrolase superfamily, residues 1333–1516) and IPR005225 (Small GTP-binding domain, residues 1334–1472), confirming catalytic GTP binding and hydrolysis. The presence of IPR032675 (Leucine-rich repeat domain superfamily, residues 940–1334) and the embedded repeats IPR003591 (Leucine-rich repeat, typical subtype, residues 1010–1291) and IPR001611 (Leucine-rich repeat, residues 1012–1267) indicates that LRR elements bridge toward the Roc–COR apparatus, likely transmitting regulatory signals from the N-terminal scaffold.

This ordered architecture dictates molecular function. The ARM/ANK scaffold recruits partners and positions substrates; the Roc–COR tandem binds and hydrolyzes GTP, driving an autoinhibitory/activating cycle; and the C-terminal kinase domain binds ATP and catalyzes phosphorylation. These features causally establish three molecular activities: GTP binding and hydrolysis (from Roc/COR and P-loop signatures), ATP binding and phosphotransfer (from the conserved kinase core and ATP-binding site), and multivalent protein binding via ARM/ANK and LRR arrays. Together they explain GO:0003824 molecular function as a kinase-centered signaling hub whose activity is gated by an intrinsic GTPase.

From these activities, the biological process emerges. A soluble serine/threonine kinase that is tightly regulated by an internal GTPase and large repeat scaffolds is archetypal for signaling assemblies that choreograph cytoskeletal dynamics, vesicle trafficking, and local phosphorylation cascades. The architecture channels information flow from GTP-driven conformational control to substrate phosphorylation, thereby modulating pathways that govern cellular organization and transport.

Cellular location follows from solubility and targeting. The absence of transmembrane segments and the dominance of ARM/ANK/LRR scaffolds argue for a soluble cytoplasmic protein that assembles complexes in the cytoplasm. This aligns with a cytoplasmic residency where phosphorylation and GTPase cycles coordinate intracellular pathways.

Mechanistically, I hypothesize that the N-terminal ARM/ANK/LRR array nucleates assembly of client proteins and adaptors; GTP binding at Roc induces a COR-mediated clamp that allosterically tunes the downstream kinase; and cycles of GTP hydrolysis reset the assembly. Substrates and partners likely include cytoskeletal regulators and trafficking factors that dock onto the repeat scaffold. In this model, transient complexes with small GTPases and adaptor proteins fine-tune kinase output in the cytoplasm.

To synthesize: the ARM/ANK and LRR scaffolds (IPR011989, IPR056597, IPR016024, IPR036770, IPR056593, IPR032675, IPR003591, IPR001611) recruit and position macromolecular assemblies; the Roc–COR GTPase engine (IPR020859, IPR027417, IPR005225, IPR032171, IPR057263) imposes nucleotide-gated control; and the C-terminal kinase apparatus (IPR051420, IPR000719, IPR011009, IPR001245, IPR017441) executes phosphorylation—together producing a cytoplasmic signaling machine whose core molecular function is captured by GO:0003824.

Functional Summary

A large cytoplasmic signaling machine that integrates a repeat-rich scaffold with an intrinsic GTPase switch and a C-terminal kinase core. The N-terminal armadillo/ankyrin and leucine-rich repeat arrays assemble and position protein complexes, while a central nucleotide-controlled Roc–COR engine tunes activity by GTP binding and hydrolysis. This gating mechanism modulates a terminal kinase module that transfers phosphate from ATP to target proteins. Together these features coordinate phosphorylation-dependent pathways that organize intracellular signaling and cytoskeletal functions within the cytoplasm.

UniProt Summary

Probable kinase that plays a role in intracellular signaling pathways.

InterPro Domains

Armadillo-like helical (IPR011989, homologous_superfamily) — residues 8-656
LRRK2, ARM repeat domain (IPR056597, domain) — residues 17-649
Armadillo-type fold (IPR016024, homologous_superfamily) — residues 172-613
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 657-803
LRRK2, ANK repeat domain (IPR056593, domain) — residues 679-808
Ser/Thr Protein Kinases with Diverse Regulatory Roles (IPR051420, family) — residues 766-2000
Leucine-rich repeat domain superfamily (IPR032675, homologous_superfamily) — residues 940-1334
Leucine-rich repeat, typical subtype (IPR003591, repeat) — residues 1010-1291
Leucine-rich repeat (IPR001611, repeat) — residues 1012-1267
Roc domain (IPR020859, domain) — residues 1328-1511
P-loop containing nucleoside triphosphate hydrolase (IPR027417, homologous_superfamily) — residues 1333-1516
Small GTP-binding domain (IPR005225, domain) — residues 1334-1472
C-terminal of Roc, COR-A domain (IPR032171, domain) — residues 1545-1671
C-terminal of Roc, COR-B domain (IPR057263, domain) — residues 1689-1858
Protein kinase domain (IPR000719, domain) — residues 1879-2000
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 1884-2000
Protein kinase, ATP binding site (IPR017441, binding_site) — residues 1885-1906
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 1885-2000

GO Terms

Molecular Function: molecular_function (GO:0003674), molecular function regulator activity (GO:0098772), binding (GO:0005488), molecular adaptor activity (GO:0060090), catalytic activity (GO:0003824), enzyme regulator activity (GO:0030234), small molecule binding (GO:0036094), organic cyclic compound binding (GO:0097159), molecular function inhibitor activity (GO:0140678), hydrolase activity (GO:0016787), ion binding (GO:0043167), catalytic activity, acting on a protein (GO:0140096), carbohydrate derivative binding (GO:0097367), protein-macromolecule adaptor activity (GO:0030674), molecular function activator activity (GO:0140677), transferase activity (GO:0016740), heterocyclic compound binding (GO:1901363), protein binding (GO:0005515), nucleoside phosphate binding (GO:1901265), protein kinase activity (GO:0004672), cation binding (GO:0043169), clathrin binding (GO:0030276), SNARE binding (GO:0000149), transferase activity, transferring phosphorus-containing groups (GO:0016772), protein dimerization activity (GO:0046983), transmembrane transporter binding (GO:0044325), enzyme binding (GO:0019899), hydrolase activity, acting on acid anhydrides (GO:0016817), signaling adaptor activity (GO:0035591), nucleoside-triphosphatase regulator activity (GO:0060589), identical protein binding (GO:0042802), anion binding (GO:0043168), enzyme inhibitor activity (GO:0004857), enzyme activator activity (GO:0008047), cytoskeletal protein binding (GO:0008092), protein kinase A binding (GO:0051018), nucleotide binding (GO:0000166), ribonucleotide binding (GO:0032553), kinase activity (GO:0016301), actin binding (GO:0003779), purine nucleotide binding (GO:0017076), GTPase regulator activity (GO:0030695), protein homodimerization activity (GO:0042803), GTPase binding (GO:0051020), purine ribonucleotide binding (GO:0032555), hydrolase activity, acting on acid anhydrides, in phosphorus-containing anhydrides (GO:0016818), metal ion binding (GO:0046872), syntaxin binding (GO:0019905), protein serine/threonine kinase activity (GO:0004674), phosphotransferase activity, alcohol group as acceptor (GO:0016773), signaling receptor complex adaptor activity (GO:0030159), GTPase activator activity (GO:0005096), tubulin binding (GO:0015631), purine ribonucleoside triphosphate binding (GO:0035639), guanyl nucleotide binding (GO:0019001), small GTPase binding (GO:0031267), syntaxin-1 binding (GO:0017075), pyrophosphatase activity (GO:0016462), GTP binding (GO:0005525), microtubule binding (GO:0008017), magnesium ion binding (GO:0000287), MAP kinase kinase kinase activity (GO:0004709), guanyl ribonucleotide binding (GO:0032561), ribonucleoside triphosphate phosphatase activity (GO:0017111), GTPase activity (GO:0003924)

Biological Process: biological_process (GO:0008150), metabolic process (GO:0008152), cellular process (GO:0009987), cellular metabolic process (GO:0044237), organic substance metabolic process (GO:0071704), primary metabolic process (GO:0044238), nitrogen compound metabolic process (GO:0006807), organonitrogen compound metabolic process (GO:1901564), protein metabolic process (GO:0019538), macromolecule metabolic process (GO:0043170), phosphorus metabolic process (GO:0006793), protein modification process (GO:0036211), phosphate-containing compound metabolic process (GO:0006796), macromolecule modification (GO:0043412), phosphorylation (GO:0016310), protein phosphorylation (GO:0006468), protein autophosphorylation (GO:0046777)

Cellular Component: cellular_component (GO:0005575), cellular anatomical entity (GO:0110165), protein-containing complex (GO:0032991), side of membrane (GO:0098552), perikaryon (GO:0043204), cell body (GO:0044297), site of polarized growth (GO:0030427), cell junction (GO:0030054), neuron projection terminus (GO:0044306), envelope (GO:0031975), endoplasmic reticulum exit site (GO:0070971), intracellular anatomical structure (GO:0005622), organelle (GO:0043226), distal axon (GO:0150034), cell projection (GO:0042995), membrane (GO:0016020), cytosol (GO:0005829), presynapse (GO:0098793), cell periphery (GO:0071944), Wnt signalosome (GO:1990909), extracellular space (GO:0005615), somatodendritic compartment (GO:0036477), cytoplasm (GO:0005737), endomembrane system (GO:0012505), extracellular region (GO:0005576), plasma membrane bounded cell projection (GO:0120025), axon terminus (GO:0043679), cytoplasmic vesicle (GO:0031410), intracellular organelle (GO:0043229), endosome (GO:0005768), synapse (GO:0045202), cytoplasmic region (GO:0099568), Golgi apparatus (GO:0005794), growth cone (GO:0030426), membrane-bounded organelle (GO:0043227), plasma membrane (GO:0005886), organelle membrane (GO:0031090), organelle envelope (GO:0031967), outer membrane (GO:0019867), cytoplasmic side of membrane (GO:0098562), extracellular organelle (GO:0043230), neuronal cell body (GO:0043025), vacuole (GO:0005773), inclusion body (GO:0016234), mitochondrion (GO:0005739), plasma membrane region (GO:0098590), endoplasmic reticulum (GO:0005783), membrane microdomain (GO:0098857), dendritic tree (GO:0097447), extracellular exosome (GO:0070062), terminal bouton (GO:0043195), membrane raft (GO:0045121), lytic vacuole (GO:0000323), mitochondrial envelope (GO:0005740), late endosome (GO:0005770), dendrite (GO:0030425), autophagosome (GO:0005776), plasma membrane raft (GO:0044853), actin-based cell projection (GO:0098858), intracellular membrane-bounded organelle (GO:0043231), bounding membrane of organelle (GO:0098588), extracellular membrane-bounded organelle (GO:0065010), neuron projection (GO:0043005), Golgi-associated vesicle (GO:0005798), organelle outer membrane (GO:0031968), plasma membrane bounded cell projection cytoplasm (GO:0032838), vesicle (GO:0031982), mitochondrial membrane (GO:0031966), mitochondrial outer membrane (GO:0005741), extracellular vesicle (GO:1903561), neuron projection cytoplasm (GO:0120111), microvillus (GO:0005902), axon (GO:0030424), multivesicular body (GO:0005771), lysosome (GO:0005764), caveola (GO:0005901), dendrite cytoplasm (GO:0032839), intracellular vesicle (GO:0097708), autolysosome (GO:0044754), secondary lysosome (GO:0005767)

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Deep Research Bioreason Rl

(LRRK2-deep-research-bioreason-rl.md)

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Exported on March 22, 2026 at 01:40 AM

Organism: Homo sapiens

Sequence:

MASGSCQGCEEDEETLKKLIVRLNNVQEGKQIETLVQILEDLLVFTYSERASKLFQGKNIHVPLLIVLDSYMRVASVQQVGWSLLCKLIEVCPGTMQSLMGPQDVGNDWEVLGVHQLILKMLTVHNASVNLSVIGLKTLDLLLTSGKITLLILDEESDIFMLIFDAMHSFPANDEVQKLGCKALHVLFERVSEEQLTEFVENKDYMILLSALTNFKDEEEIVLHVLHCLHSLAIPCNNVEVLMSGNVRCYNIVVEAMKAFPMSERIQEVSCCLLHRLTLGNFFNILVLNEVHEFVVKAVQQYPENAALQISALSCLALLTETIFLNQDLEEKNENQENDDEGEEDKLFWLEACYKALTWHRKNKHVQEAACWALNNLLMYQNSLHEKIGDEDGHFPAHREVMLSMLMHSSSKEVFQASANALSTLLEQNVNFRKILLSKGIHLNVLELMQKHIHSPEVAESGCKMLNHLFEGSNTSLDIMAAVVPKILTVMKRHETSLPVQLEALRAILHFIVPGMPEESREDTEFHHKLNMVKKQCFKNDIHKLVLAALNRFIGNPGIQKCGLKVISSIVHFPDALEMLSLEGAMDSVLHTLQMYPDDQEIQCLGLSLIGYLITKKNVFIGTGHLLAKILVSSLYRFKDVAEIQTKGFQTILAILKLSASFSKLLVHHSFDLVIFHQMSSNIMEQKDQQFLNLCCKCFAKVAMDDYLKNVMLERACDQNNSIMVECLLLLGADANQAKEGSSLICQVCEKESSPKLVELLLNSGSREQDVRKALTISIGKGDSQIISLLLRRLALDVANNSICLGGFCIGKVEPSWLGPLFPDKTSNLRKQTNIASTLARMVIRYQMKSAVEEGTASGSDGNFSEDVLSKFDEWTFIPDSSMDSVFAQSDDLDSEGSEGSFLVKKKSNSISVGEFYRDAVLQRCSPNLQRHSNSLGPIFDHEDLLKRKRKILSSDDSLRSSKLQSHMRHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNV

Thinking Trace

Functional Summary

UniProt Summary

Probable kinase that plays a role in intracellular signaling pathways.

InterPro Domains

Armadillo-like helical (IPR011989, homologous_superfamily) — residues 8-656
LRRK2, ARM repeat domain (IPR056597, domain) — residues 17-649
Armadillo-type fold (IPR016024, homologous_superfamily) — residues 172-613
Ankyrin repeat-containing domain superfamily (IPR036770, homologous_superfamily) — residues 657-803
LRRK2, ANK repeat domain (IPR056593, domain) — residues 679-808
Ser/Thr Protein Kinases with Diverse Regulatory Roles (IPR051420, family) — residues 766-2000
Leucine-rich repeat domain superfamily (IPR032675, homologous_superfamily) — residues 940-1334
Leucine-rich repeat, typical subtype (IPR003591, repeat) — residues 1010-1291
Leucine-rich repeat (IPR001611, repeat) — residues 1012-1267
Roc domain (IPR020859, domain) — residues 1328-1511
P-loop containing nucleoside triphosphate hydrolase (IPR027417, homologous_superfamily) — residues 1333-1516
Small GTP-binding domain (IPR005225, domain) — residues 1334-1472
C-terminal of Roc, COR-A domain (IPR032171, domain) — residues 1545-1671
C-terminal of Roc, COR-B domain (IPR057263, domain) — residues 1689-1858
Protein kinase domain (IPR000719, domain) — residues 1879-2000
Protein kinase-like domain superfamily (IPR011009, homologous_superfamily) — residues 1884-2000
Protein kinase, ATP binding site (IPR017441, binding_site) — residues 1885-1906
Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245, domain) — residues 1885-2000

GO Terms

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Deep Research Falcon

(LRRK2-deep-research-falcon.md)

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organism: human
gene_id: LRRK2
gene_symbol: LRRK2
uniprot_accession: Q5S007
protein_description: 'RecName: Full=Leucine-rich repeat serine/threonine-protein
kinase 2; EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718,
ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815,
ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}; EC=3.6.5.- {ECO:0000269|PubMed:18230735,
ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462,
ECO:0000269|PubMed:29212815}; AltName: Full=Dardarin;'
gene_info: Name=LRRK2; Synonyms=PARK8;
organism_full: Homo sapiens (Human).
protein_family: Belongs to the protein kinase superfamily. TKL Ser/Thr
protein_domains: ANK_LRRK2. (IPR056593); Ankyrin_rpt-contain_sf. (IPR036770); ARM-like.
(IPR011989); ARM-type_fold. (IPR016024); ARM_LRRK2. (IPR056597)
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q5S007
Protein Description: RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}; EC=3.6.5.- {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815}; AltName: Full=Dardarin;
Gene Information: Name=LRRK2; Synonyms=PARK8;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. TKL Ser/Thr
Key Domains: ANK_LRRK2. (IPR056593); Ankyrin_rpt-contain_sf. (IPR036770); ARM-like. (IPR011989); ARM-type_fold. (IPR016024); ARM_LRRK2. (IPR056597)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "LRRK2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'LRRK2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene LRRK2 (gene ID: LRRK2, UniProt: Q5S007) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q5S007
Protein Description: RecName: Full=Leucine-rich repeat serine/threonine-protein kinase 2; EC=2.7.11.1 {ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29127255, ECO:0000269|PubMed:29212815, ECO:0000269|PubMed:30398148, ECO:0000269|PubMed:30635421}; EC=3.6.5.- {ECO:0000269|PubMed:18230735, ECO:0000269|PubMed:26824392, ECO:0000269|PubMed:28720718, ECO:0000269|PubMed:29125462, ECO:0000269|PubMed:29212815}; AltName: Full=Dardarin;
Gene Information: Name=LRRK2; Synonyms=PARK8;
Organism (full): Homo sapiens (Human).
Protein Family: Belongs to the protein kinase superfamily. TKL Ser/Thr
Key Domains: ANK_LRRK2. (IPR056593); Ankyrin_rpt-contain_sf. (IPR036770); ARM-like. (IPR011989); ARM-type_fold. (IPR016024); ARM_LRRK2. (IPR056597)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "LRRK2" matches the protein description above
Verify the organism is correct: Homo sapiens (Human).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene LRRK2 (gene ID: LRRK2, UniProt: Q5S007) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Plan status and verification
- Target identity verification: The report focuses on human LRRK2 (UniProt Q5S007), also known as dardarin/PARK8. Literature and structural studies consistently describe a large ROCO-family protein with N‑terminal ARM/ANK/LRR repeats, a central ROC (GTPase) and COR tandem, followed by a Ser/Thr kinase domain and C‑terminal WD40 domain. Dual catalytic activities—protein kinase (EC 2.7.11.1) and ROC GTPase (EC 3.6.5.-)—are well established (gilsbach2024intramolecularfeedbackregulation pages 16-17, dzamko2025leucinerichrepeatkinase pages 9-10).

Key concepts and definitions (current understanding)
- Structure and domains: LRRK2 is a multi-domain ROCO protein with ARM/ANK/LRR–ROC–COR–kinase–WD40 architecture. The ROC-COR tandem regulates the kinase; interdomain cross-talk shapes activation state and oligomerization (e.g., dimerization) (gilsbach2024intramolecularfeedbackregulation pages 16-17). 14‑3‑3 proteins bind phosphorylated sites in the N‑terminus (Ser910/Ser935 cluster), stabilizing an inactive state (dzamko2025leucinerichrepeatkinase pages 9-10).
- Catalytic activities: LRRK2 is a Ser/Thr kinase and a small GTPase (ROC). Intramolecular feedback regulates the ROC GTPase by kinase-dependent autophosphorylation (e.g., ROC P‑loop T1343) affecting GTPase kinetics and monomer–dimer equilibrium (gilsbach2024intramolecularfeedbackregulation pages 16-17). Autophosphorylation at Ser1292 is a readout of kinase activity (dzamko2025leucinerichrepeatkinase pages 9-10).
- Primary substrates and substrate specificity: Phosphoproteomics and targeted studies define a subset of Rab GTPases as primary physiologic substrates, with Rab10 Thr73 the prototypic site; additional validated Rabs include Rab8A/B, Rab12, Rab29, Rab35, Rab43. Phospho‑Rab readouts are robust biomarkers of LRRK2 pathway activity in cells and biofluids (dzamko2025leucinerichrepeatkinase pages 2-4, lozano2024theroleofb pages 51-53, lozano2024theroleofa pages 51-53).
- Regulation: (i) 14‑3‑3 binding to the Ser910/Ser935 cluster is modulated by upstream kinases and disrupted by some PD‑linked LRRK2 variants; it provides a pharmacodynamic (PD) readout for inhibitors. (ii) Ser1292 autophosphorylation scales with pathogenic activation. (iii) Rab29-mediated recruitment/activation at the Golgi has been reported. (iv) Kinase↔GTPase cross‑talk within ROC‑COR‑kinase controls activity and oligomerization. (v) Redox-sensitive “CC” motif (C2024/C2025) in the activation segment modulates kinase activity and microtubule docking in response to oxidants/reductants (dzamko2025leucinerichrepeatkinase pages 9-10, gilsbach2024intramolecularfeedbackregulation pages 16-17).
- Cellular localization: LRRK2 is largely cytosolic but dynamically recruited to membranes where Rab substrates reside: Golgi, endosomes/lysosomes, and phagosomes. Under certain conditions and with specific inhibitor types, microtubule association and filament formation can occur, though endogenous detection varies across systems (dzamko2025leucinerichrepeatkinase pages 9-10, gilsbach2024intramolecularfeedbackregulation pages 16-17, dzamko2025leucinerichrepeatkinase pages 8-9).

Recent developments and latest research (emphasis 2023–2024)
- Intramolecular feedback and structural crosstalk: 2024 eLife work shows kinase-dependent phosphorylation of ROC (T1343) drives feedback on GTPase kinetics and monomer–dimer balance, advancing understanding of ROC–COR–kinase communication (Dec 2024; https://doi.org/10.7554/eLife.91083.4) (gilsbach2024intramolecularfeedbackregulation pages 16-17).
- Redox control of the kinase: 2024 NPJ Parkinson’s Disease identified a unique CC motif (C2024/C2025) in the activation segment that differentially contributes to catalysis (C2024 essential) and redox sensitivity (C2025), suggesting oxidative agents can downregulate hyperactive LRRK2 (Apr 2024; https://doi.org/10.1038/s41531-024-00683-5) (dzamko2025leucinerichrepeatkinase pages 9-10).
- Rab phosphorylation as core readout: Reviews and mechanistic syntheses reaffirm Rab10 Thr73 and other Rabs as endogenous substrates; phospho‑Rab immunoassays in immune cells are advancing to clinical PD biomarker use (Biochem J review, May 2025, references therein with earlier primary studies; https://doi.org/10.1042/BCJ20253099) (dzamko2025leucinerichrepeatkinase pages 2-4, dzamko2025leucinerichrepeatkinase pages 9-10).
- Ciliogenesis pathway: Rab8/Rab10 phosphorylation drives centrosomal cohesion and primary cilia deficits through RILPL1; this mechanistic axis continues to underpin cell‑type specific cilia phenotypes in disease models and patient cells (Human Mol Genet Aug 2019; https://doi.org/10.1093/hmg/ddz201; with 2023–2024 reviews expanding context) (ordonez2019rab8rab10and pages 32-33, lozano2024theroleofb pages 51-53).

Current applications and real‑world implementations
- Biomarkers: Peripheral immune-cell biomarkers include pRab10 Thr73 (typically measured in neutrophils/monocytes) and LRRK2 Ser935 phosphorylation; these show acceptable within‑subject variability and are used as PD biomarkers and for target engagement in early‑phase trials (Clinical & Translational Science May 2023; https://doi.org/10.1111/cts.13541; Biochem J May 2025; https://doi.org/10.1042/BCJ20253099) (dzamko2025leucinerichrepeatkinase pages 2-4). Autophosphorylation at Ser1292 has been detected in exosomes/CSF but is low abundance and technically challenging (dzamko2025leucinerichrepeatkinase pages 9-10).
- Drug development: Small‑molecule LRRK2 kinase inhibitors (e.g., type 1 ATP-competitive inhibitors including DNL151/BIIB122) have entered human studies; pSer935 and pRab10 serve as PD biomarkers for target engagement and dose–response (Biochem J review citing 2023–2024 clinical reports; https://doi.org/10.1042/BCJ20253099) (dzamko2025leucinerichrepeatkinase pages 8-9, dzamko2025leucinerichrepeatkinase pages 2-4). Type 2 inhibitors are being explored with distinct effects on pSer935 (dzamko2025leucinerichrepeatkinase pages 9-10).

Expert opinions and analysis from authoritative sources
- Dzamko 2025 review: Recommends multi‑matrix (blood/urine/CSF) biomarker panels that combine pRab10, pSer935, and downstream lysosomal readouts; emphasizes that most human studies to date are small and require multi‑site validation and longitudinal design (May 2025; https://doi.org/10.1042/BCJ20253099) (dzamko2025leucinerichrepeatkinase pages 8-9, dzamko2025leucinerichrepeatkinase pages 9-10).
- Mechanistic consensus: Rab GTPases are the principal substrates linking LRRK2 to endolysosomal trafficking and ciliogenesis; 14‑3‑3 binding to N‑terminal phosphosites stabilizes inactive conformations and is a reliable pharmacodynamic signal for type 1 inhibitors (dzamko2025leucinerichrepeatkinase pages 9-10, dzamko2025leucinerichrepeatkinase pages 2-4).

Relevant statistics and quantitative data
- Substrate breadth: Screens of 50 Rab proteins identified phosphorylation of 14 when overexpressed and evidence for at least 10 endogenous Rabs (including Rab8A/B, Rab10, Rab12, Rab29, Rab35, Rab43) as LRRK2 substrates (citations summarized in 2024 overview) (lozano2024theroleofa pages 51-53, lozano2024theroleof pages 51-53).
- Biomarker variability: Within‑subject geometric CVs across matrices ranged ~13–51% (whole blood/neutrophils) and higher in PBMCs (35–274%); between‑subject variability was lower in neutrophils/whole blood (45–123%) relative to PBMCs (190–415%) in a 2023 PD cohort (Clinical & Translational Science; https://doi.org/10.1111/cts.13541) (dzamko2025leucinerichrepeatkinase pages 2-4).

Functional roles, localization, and pathways
- Endolysosomal/Golgi trafficking: Pathogenic LRRK2 perturbs Golgi‑to‑lysosome traffic, retromer function (via Rab29), and lysosomal enzyme regulation (e.g., GCase), consistent with Rab substrate phosphorylation. LRRK2 concentrates at membranes of the endolysosomal system where these substrates reside (lozano2024theroleofb pages 51-53, lozano2024theroleofa pages 51-53, lozano2024theroleof pages 51-53).
- Ciliogenesis and centrosomal cohesion: LRRK2‑mediated phosphorylation of Rab8/Rab10 drives centrosomal accumulation and RILPL1‑dependent ciliogenesis defects; inhibition of LRRK2 rescues these phenotypes in cells and animal models (Human Mol Genet 2019; https://doi.org/10.1093/hmg/ddz201) (ordonez2019rab8rab10and pages 32-33).
- Biomarker and PD readouts: pRab10 (Thr73) in immune cells and pSer935 on LRRK2 are the most practical PD/TE biomarkers; Ser1292 autophosphorylation is informative but technically demanding (dzamko2025leucinerichrepeatkinase pages 2-4, dzamko2025leucinerichrepeatkinase pages 9-10).

Embedded quick‑reference artifact
| Category | Detail | Evidence/notes | Key recent sources (with DOI URLs) |
|---|---|---|---|
| Identity | Human LRRK2 — gene LRRK2; UniProt Q5S007; large multi‑domain ROCO family protein (aka dardarin/PARK8) | Identity and nomenclature confirmed across literature; widely studied in human Parkinson's disease context (lozano2024theroleof pages 51-53, gilsbach2024intramolecularfeedbackregulation pages 16-17) | Dzamko N. Biochem J. 2025. https://doi.org/10.1042/bcj20253099; Gilsbach et al., eLife 2024. https://doi.org/10.7554/eLife.91083.4 |
| Domain architecture | N‑terminal ARM/ANK/LRR repeats — ROC (GTPase) — COR tandem — Ser/Thr kinase domain — C‑terminal WD40 (ARM/ANK/LRR/ROC–COR–KIN–WD40) | Domain map from structural and biochemical studies; full‑length and domain structures document this organization (gilsbach2024intramolecularfeedbackregulation pages 16-17, lozano2024theroleofa pages 51-53) | Gilsbach et al., eLife 2024. https://doi.org/10.7554/eLife.91083.4; Myasnikov et al. (gilsbach2024intramolecularfeedbackregulation pages 16-17) |
| Catalytic activities | Dual enzymatic functions: Ser/Thr protein kinase (EC 2.7.11.1) and Roc GTPase (EC 3.6.5.-); intramolecular cross‑talk modulates activities | Dual activity and feedback between ROC–COR and kinase domains demonstrated biochemically and structurally (gilsbach2024intramolecularfeedbackregulation pages 16-17) | Gilsbach et al., eLife 2024. https://doi.org/10.7554/eLife.91083.4; (reviews collated in Dzamko 2025) https://doi.org/10.1042/bcj20253099 |
| Primary substrates | Selected physiologic substrates: Rab GTPases — Rab10 (Thr73), Rab8A/B, Rab12, Rab29, Rab35, Rab43 (phospho‑Rab readouts used as activity biomarkers) | Phosphoproteomics and targeted studies validated Rab10 Thr73 and multiple Rabs as direct LRRK2 kinase substrates (lozano2024theroleofb pages 51-53, lozano2024theroleofa pages 51-53, dzamko2025leucinerichrepeatkinase pages 2-4) | Ordóñez et al., Hum Mol Genet 2019. https://doi.org/10.1093/hmg/ddz201; Dzamko 2025. https://doi.org/10.1042/bcj20253099 |
| Regulatory mechanisms | 1) 14‑3‑3 binding regulated by N‑terminal phospho‑cluster (Ser910/Ser935/Ser955/Ser973); 2) Ser1292 autophosphorylation as activity marker; 3) Rab29 recruits/activates LRRK2 at Golgi; 4) ROC–COR–kinase intramolecular crosstalk; 5) redox-sensitive CC motif (C2024/C2025) modulates kinase/redox response | Multiple biochemical and structural reports document these controls and mutation effects on regulation (dzamko2025leucinerichrepeatkinase pages 9-10, gilsbach2024intramolecularfeedbackregulation pages 16-17, lozano2024theroleof pages 51-53) | Dzamko 2025. https://doi.org/10.1042/bcj20253099; Gilsbach et al., eLife 2024. https://doi.org/10.7554/eLife.91083.4; Trilling et al., NPJ PD 2024. https://doi.org/10.1038/s41531-024-00683-5 |
| Localization | Predominantly cytosolic but recruited to membranes (Golgi, endosomes/lysosomes, phagosomes); under some conditions associates with microtubules and forms filaments (not always detected at endogenous levels) | Cell and in situ structural/biochemical studies show dynamic cytosol↔membrane localization and stimulus‑dependent membrane recruitment (lozano2024theroleof pages 51-53, gilsbach2024intramolecularfeedbackregulation pages 16-17, dzamko2025leucinerichrepeatkinase pages 8-9) | Dzamko 2025. https://doi.org/10.1042/bcj20253099; Chen et al. (cryo‑ET studies cited in gathered evidence) https://doi.org/10.7554/eLife.100799 (dzamko2025leucinerichrepeatkinase pages 8-9) |
| Pathways / cellular roles | Endolysosomal and Golgi–lysosome trafficking, regulation of lysosomal homeostasis (LYTL — LRRK2‑driven lysosomal tubulation/sorting), ciliogenesis/centrosomal cohesion via phospho‑Rab10→RILPL1 axis, impacts on synaptic vesicle endocytosis and autophagy | Mechanistic links between Rab phosphorylation and disrupted trafficking/ciliogenesis/lysosomal function established in cellular, animal, and patient‑derived studies (ordonez2019rab8rab10and pages 32-33, lozano2024theroleofb pages 51-53, lozano2024theroleof pages 51-53) | Ordóñez et al., Hum Mol Genet 2019. https://doi.org/10.1093/hmg/ddz201; Bonet‑Ponce & Cookson reviews (lozano2024theroleof pages 51-53); Dzamko 2025. https://doi.org/10.1042/bcj20253099 |

Table: Compact reference table summarizing human LRRK2 identity, domains, enzymatic activities, main substrates, regulation, localization and key pathways with evidence notes and recent DOI‑linked sources for rapid use in functional annotation and translational planning.

URLs and publication dates (selected, recent/authoritative)
- Dzamko N (Review) “Leucine-rich repeat kinase 2 biomarkers for Parkinson’s disease.” Biochemical Journal, 482:709–720 (May 2025). URL: https://doi.org/10.1042/BCJ20253099 (supports biomarkers, regulation, translational context) (dzamko2025leucinerichrepeatkinase pages 9-10, dzamko2025leucinerichrepeatkinase pages 2-4, dzamko2025leucinerichrepeatkinase pages 8-9).
- Gilsbach BK et al. “Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase-dependent mechanism.” eLife (Dec 2024). URL: https://doi.org/10.7554/eLife.91083.4 (supports ROC–COR–kinase cross‑talk) (gilsbach2024intramolecularfeedbackregulation pages 16-17).
- Trilling CR et al. “RedOx regulation of LRRK2 kinase activity by active site cysteines.” NPJ Parkinson’s Disease 10 (Apr 2024). URL: https://doi.org/10.1038/s41531-024-00683-5 (supports redox CC motif) (dzamko2025leucinerichrepeatkinase pages 9-10).
- Ordóñez AJL et al. “RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase–mediated centrosomal cohesion and ciliogenesis deficits.” Human Molecular Genetics 28:3552–3568 (Aug 2019). URL: https://doi.org/10.1093/hmg/ddz201 (mechanistic pathway for ciliogenesis/cilia loss) (ordonez2019rab8rab10and pages 32-33).
- Lozano MR (2024 synopsis). “The role of RAB10 and RAB29 in endolysosomal trafficking alterations mediated by pathogenic LRRK2.” (2024). Evidence compiled on Rab substrates, 14‑3‑3 regulation, Golgi/lysosome trafficking (lozano2024theroleofb pages 51-53, lozano2024theroleofa pages 51-53, lozano2024theroleof pages 51-53).
- Vissers MFJM et al. “LRRK2 pathway biomarker characterization study…” Clinical and Translational Science 16:1408–1420 (May 2023). URL: https://doi.org/10.1111/cts.13541 (biomarker variability across matrices) (dzamko2025leucinerichrepeatkinase pages 2-4).

Conclusion
- The human LRRK2 protein (Q5S007) is a dual‑enzyme ROCO protein that phosphorylates a defined subset of Rab GTPases, coupling cytosolic→membrane localization to control endolysosomal and Golgi–lysosome trafficking and ciliogenesis. Regulation integrates 14‑3‑3 binding at N‑terminal phosphosites, autophosphorylation, Rab29‑mediated recruitment, redox‑sensitive residues, and ROC–COR–kinase domain cross‑talk. Translationally, pRab10 and pSer935 are practical biomarkers for pathway activity and target engagement; type‑1 LRRK2 inhibitors have advanced into early clinical testing with these pharmacodynamic readouts. Larger, multi‑site human studies are a current need to validate biomarker–disease relationships and optimize trial design (dzamko2025leucinerichrepeatkinase pages 9-10, dzamko2025leucinerichrepeatkinase pages 2-4, dzamko2025leucinerichrepeatkinase pages 8-9).

References

(gilsbach2024intramolecularfeedbackregulation pages 16-17): Bernd K Gilsbach, Franz Y Ho, Benjamin Riebenbauer, Xiaojuan Zhang, Giambattista Guaitoli, Arjan Kortholt, and Christian Johannes Gloeckner. Intramolecular feedback regulation of the lrrk2 roc g domain by a lrrk2 kinase-dependent mechanism. eLife, Dec 2024. URL: https://doi.org/10.7554/elife.91083.4, doi:10.7554/elife.91083.4. This article has 5 citations and is from a domain leading peer-reviewed journal.
(dzamko2025leucinerichrepeatkinase pages 9-10): Nicolas Dzamko. Leucine-rich repeat kinase 2 biomarkers for parkinson’s disease. Biochemical Journal, 482:709-720, May 2025. URL: https://doi.org/10.1042/bcj20253099, doi:10.1042/bcj20253099. This article has 2 citations and is from a domain leading peer-reviewed journal.
(dzamko2025leucinerichrepeatkinase pages 2-4): Nicolas Dzamko. Leucine-rich repeat kinase 2 biomarkers for parkinson’s disease. Biochemical Journal, 482:709-720, May 2025. URL: https://doi.org/10.1042/bcj20253099, doi:10.1042/bcj20253099. This article has 2 citations and is from a domain leading peer-reviewed journal.
(lozano2024theroleofb pages 51-53): M Romo Lozano. The role of rab10 and rab29 in endolysosomal trafficking alterations mediated by pathogenic lrrk2. Unknown journal, 2024.
(lozano2024theroleofa pages 51-53): M Romo Lozano. The role of rab10 and rab29 in endolysosomal trafficking alterations mediated by pathogenic lrrk2. Unknown journal, 2024.
(dzamko2025leucinerichrepeatkinase pages 8-9): Nicolas Dzamko. Leucine-rich repeat kinase 2 biomarkers for parkinson’s disease. Biochemical Journal, 482:709-720, May 2025. URL: https://doi.org/10.1042/bcj20253099, doi:10.1042/bcj20253099. This article has 2 citations and is from a domain leading peer-reviewed journal.
(ordonez2019rab8rab10and pages 32-33): Antonio Jesús Lara Ordónez, Belén Fernández, Elena Fdez, María Romo-Lozano, Jesús Madero-Pérez, Evy Lobbestael, Veerle Baekelandt, Ana Aiastui, Adolfo López de Munaín, Heather L Melrose, Laura Civiero, and Sabine Hilfiker. Rab8, rab10 and rilpl1 contribute to both lrrk2 kinase–mediated centrosomal cohesion and ciliogenesis deficits. Human Molecular Genetics, 28:3552-3568, Aug 2019. URL: https://doi.org/10.1093/hmg/ddz201, doi:10.1093/hmg/ddz201. This article has 90 citations and is from a domain leading peer-reviewed journal.
(lozano2024theroleof pages 51-53): M Romo Lozano. The role of rab10 and rab29 in endolysosomal trafficking alterations mediated by pathogenic lrrk2. Unknown journal, 2024.

Citations

gilsbach2024intramolecularfeedbackregulation pages 16-17
dzamko2025leucinerichrepeatkinase pages 9-10
dzamko2025leucinerichrepeatkinase pages 2-4
dzamko2025leucinerichrepeatkinase pages 8-9
lozano2024theroleof pages 51-53
lozano2024theroleofb pages 51-53
lozano2024theroleofa pages 51-53
https://doi.org/10.7554/eLife.91083.4
https://doi.org/10.1038/s41531-024-00683-5
https://doi.org/10.1042/BCJ20253099
https://doi.org/10.1093/hmg/ddz201;
https://doi.org/10.1111/cts.13541;
https://doi.org/10.1111/cts.13541
https://doi.org/10.1093/hmg/ddz201
https://doi.org/10.1042/bcj20253099;
https://doi.org/10.7554/eLife.91083.4;
https://doi.org/10.1042/bcj20253099
https://doi.org/10.7554/eLife.100799
https://doi.org/10.7554/elife.91083.4,
https://doi.org/10.1042/bcj20253099,
https://doi.org/10.1093/hmg/ddz201,

Bioreason Rl Review

(LRRK2-bioreason-rl-review.md)

BioReason-Pro RL Review: LRRK2 (human)

Source: LRRK2-deep-research-bioreason-rl.md

Correctness: 4/5
Completeness: 3/5

Functional Summary Review

The BioReason functional summary states:

A large cytoplasmic signaling machine that integrates a repeat-rich scaffold with an intrinsic GTPase switch and a C-terminal kinase core. The N-terminal armadillo/ankyrin and leucine-rich repeat arrays assemble and position protein complexes, while a central nucleotide-controlled Roc-COR engine tunes activity by GTP binding and hydrolysis. This gating mechanism modulates a terminal kinase module that transfers phosphate from ATP to target proteins. Together these features coordinate phosphorylation-dependent pathways that organize intracellular signaling and cytoskeletal functions within the cytoplasm.

This is a strong summary that correctly identifies all major functional domains of LRRK2: ARM repeats, ANK repeats, LRR domain, Roc GTPase, COR domain, and kinase domain. The description of the GTPase-kinase coupling mechanism is accurate and matches the curated review's accepted annotations for GTPase activity (GO:0003924), GTP binding (GO:0005525), protein kinase activity (GO:0004672), and protein serine/threonine kinase activity (GO:0004674).

The curated review describes LRRK2 as a multidomain protein with kinase and GTPase activities whose core functions include intracellular signal transduction (GO:0035556), vesicle-mediated transport (GO:0016192), and Golgi organization (GO:0007030). BioReason captures the kinase-GTPase coupling and cytoskeletal signaling themes but misses the specific vesicle trafficking and Golgi functions.

Key gaps:
1. LRRK2's well-characterized role in vesicle trafficking, particularly Rab GTPase phosphorylation (Rab8A, Rab10, etc.), is not mentioned
2. The lysosomal biology and autophagy connections are absent
3. The Parkinson disease context and neuronal function specificity are not captured

Comparison with interpro2go:

The curated review does not specifically flag GO_REF:0000002 annotations but includes IEA annotations for kinase and GTPase activities. BioReason's reasoning closely tracks what interpro2go would derive from the kinase domain (IPR000719) and Roc domain (IPR020859): protein kinase activity, GTPase activity, and ATP/GTP binding. BioReason adds the structural narrative about the ARM/ANK/LRR scaffold as a partner-recruitment platform, which goes modestly beyond interpro2go. However, the specific biological processes (Rab phosphorylation, vesicle trafficking) are not derivable from domain architecture alone.

Notes on thinking trace

The trace demonstrates thorough dissection of all major domains and their spatial arrangement. The mechanistic hypothesis about GTP hydrolysis resetting kinase assemblies is reasonable. The assignment of GO:0003824 (catalytic activity) as the "core molecular function" is surprisingly generic given that more specific terms are clearly supported by the domain analysis.

📄 View Raw YAML

id: Q5S007
gene_symbol: LRRK2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: LRRK2 (Leucine-rich repeat serine/threonine-protein kinase 2) is a large multi-domain ROCO family protein with dual enzymatic activities - a serine/threonine protein kinase (EC 2.7.11.1) and a GTPase (EC 3.6.5.-). The protein contains ARM/ANK/LRR repeats, ROC (Ras of complex proteins) GTPase domain, COR (C-terminal of ROC) domain, kinase domain, and WD40 repeats. LRRK2 phosphorylates a subset of Rab GTPases (primarily Rab8A, Rab10, Rab12, Rab29) at their switch II regions, regulating endolysosomal trafficking and ciliogenesis. It is predominantly cytosolic but dynamically recruited to Golgi, endosomes, and lysosomes where its Rab substrates reside. Mutations in LRRK2 are the most common genetic cause of familial Parkinson's disease (PARK8).
existing_annotations:
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: LRRK2 is a multi-domain ROCO protein kinase that phosphorylates Rab GTPases (Rab8, Rab10, Rab12, Rab29) to regulate endolysosomal trafficking and ciliogenesis. This broad BP term accurately captures its signaling role.
    action: ACCEPT
    reason: LRRK2 functions as a serine/threonine kinase that transduces signals by phosphorylating Rab GTPases, thereby regulating downstream cellular processes. The IBA annotation is appropriate as LRRK2 is clearly involved in intracellular signal transduction via its kinase and GTPase activities.
    supported_by:
    - reference_id: PMID:30398148
      supporting_text: Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10.
    - reference_id: file:human/LRRK2/LRRK2-deep-research-falcon.md
      supporting_text: 'model: Edison Scientific Literature'
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Dendrite localization is tissue-specific in neurons, not a core localization.
    action: KEEP_AS_NON_CORE
    reason: Dendrite localization is tissue-specific in neurons, not a core localization.
- term:
    id: GO:0007029
    label: endoplasmic reticulum organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
    action: ACCEPT
    reason: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
    action: ACCEPT
    reason: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
- term:
    id: GO:0031344
    label: regulation of cell projection organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulation of cell projection organization - includes ciliogenesis.
    action: ACCEPT
    reason: Regulation of cell projection organization - includes ciliogenesis.
- term:
    id: GO:0060159
    label: regulation of dopamine receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulation of dopamine receptor signaling pathway - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dopamine receptor signaling pathway - tissue-specific.
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
    action: KEEP_AS_NON_CORE
    reason: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
- term:
    id: GO:1900242
    label: regulation of synaptic vesicle endocytosis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Regulation of synaptic vesicle endocytosis - well-documented LRRK2 function.
    action: ACCEPT
    reason: Regulation of synaptic vesicle endocytosis - well-documented LRRK2 function.
- term:
    id: GO:0004706
    label: JUN kinase kinase kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: JUN kinase kinase kinase activity - reported but may not be physiological core function.
    action: UNDECIDED
    reason: JUN kinase kinase kinase activity - reported but may not be physiological core function.
- term:
    id: GO:0098794
    label: postsynapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: Postsynapse is a tissue-specific neuronal localization.
    action: KEEP_AS_NON_CORE
    reason: Postsynapse is a tissue-specific neuronal localization.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Golgi membrane localization - LRRK2 is recruited to Golgi membranes where Rab29 resides.
    action: ACCEPT
    reason: Golgi membrane localization - LRRK2 is recruited to Golgi membranes where Rab29 resides.
- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Nucleotide binding - required for kinase and GTPase activities.
    action: ACCEPT
    reason: Nucleotide binding - required for kinase and GTPase activities.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: GTPase activity is a core function of LRRK2 ROC domain. The ROC domain binds and hydrolyzes GTP.
    action: ACCEPT
    reason: GTPase activity is a core function of LRRK2 ROC domain. The ROC domain binds and hydrolyzes GTP.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
- term:
    id: GO:0005096
    label: GTPase activator activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: GTPase activator activity - LRRK2 has intrinsic GTPase activity but GAP activity on other GTPases is unclear.
    action: UNDECIDED
    reason: GTPase activator activity - LRRK2 has intrinsic GTPase activity but GAP activity on other GTPases is unclear.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ATP binding is required for LRRK2 kinase activity.
    action: ACCEPT
    reason: ATP binding is required for LRRK2 kinase activity.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    action: ACCEPT
    reason: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Mitochondrial outer membrane - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial outer membrane - reported but may be minor.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Lysosome localization is consistent with LRRK2 role in endolysosomal trafficking.
    action: ACCEPT
    reason: Lysosome localization is consistent with LRRK2 role in endolysosomal trafficking.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Endosome localization is consistent with LRRK2 role in regulating Rab-dependent trafficking.
    action: ACCEPT
    reason: Endosome localization is consistent with LRRK2 role in regulating Rab-dependent trafficking.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: ER membrane - related to ER exit site function.
    action: KEEP_AS_NON_CORE
    reason: ER membrane - related to ER exit site function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Cytoskeleton - microtubule association documented.
    action: KEEP_AS_NON_CORE
    reason: Cytoskeleton - microtubule association documented.
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Autophagy effects are downstream of LRRK2 trafficking disruption, not a direct evolved function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Autophagy effects are downstream of LRRK2 trafficking disruption, not a direct evolved function.
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
    action: ACCEPT
    reason: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
- term:
    id: GO:0007166
    label: cell surface receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Cell surface receptor signaling pathway - very broad.
    action: KEEP_AS_NON_CORE
    reason: Cell surface receptor signaling pathway - very broad.
- term:
    id: GO:0009653
    label: anatomical structure morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Anatomical structure morphogenesis is very broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: Anatomical structure morphogenesis is very broad.
- term:
    id: GO:0009968
    label: negative regulation of signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Negative regulation of signal transduction - broad.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of signal transduction - broad.
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of gene expression - very broad downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of gene expression - very broad downstream effect.
- term:
    id: GO:0016192
    label: vesicle-mediated transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Vesicle-mediated transport - core function via Rab GTPase phosphorylation regulating trafficking.
    action: ACCEPT
    reason: Vesicle-mediated transport - core function via Rab GTPase phosphorylation regulating trafficking.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
    action: ACCEPT
    reason: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Transferase activity - parent term of kinase activity.
    action: ACCEPT
    reason: Transferase activity - parent term of kinase activity.
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Hydrolase activity - parent term of GTPase activity.
    action: ACCEPT
    reason: Hydrolase activity - parent term of GTPase activity.
- term:
    id: GO:0030154
    label: cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Cell differentiation is very broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cell differentiation is very broad.
- term:
    id: GO:0030159
    label: signaling receptor complex adaptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Signaling receptor complex adaptor activity - Wnt scaffold role.
    action: UNDECIDED
    reason: Signaling receptor complex adaptor activity - Wnt scaffold role.
- term:
    id: GO:0030162
    label: regulation of proteolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of proteolysis - broad.
    action: KEEP_AS_NON_CORE
    reason: Regulation of proteolysis - broad.
- term:
    id: GO:0030182
    label: neuron differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Neuron differentiation is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Neuron differentiation is developmental.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Axon localization is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Axon localization is tissue-specific in neurons.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Dendrite localization is tissue-specific in neurons, not a core localization.
    action: KEEP_AS_NON_CORE
    reason: Dendrite localization is tissue-specific in neurons, not a core localization.
- term:
    id: GO:0030672
    label: synaptic vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Synaptic vesicle membrane is tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle membrane is tissue-specific.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Cytoplasmic vesicle - consistent with trafficking role.
    action: ACCEPT
    reason: Cytoplasmic vesicle - consistent with trafficking role.
- term:
    id: GO:0035640
    label: exploration behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Exploration behavior is a high-level organismal phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exploration behavior is a high-level organismal phenotype.
- term:
    id: GO:0042391
    label: regulation of membrane potential
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of membrane potential - neuronal effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of membrane potential - neuronal effect.
- term:
    id: GO:0043195
    label: terminal bouton
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Terminal bouton is tissue-specific neuronal localization.
    action: KEEP_AS_NON_CORE
    reason: Terminal bouton is tissue-specific neuronal localization.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Perikaryon (neuronal cell body) is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Perikaryon (neuronal cell body) is tissue-specific localization.
- term:
    id: GO:0045335
    label: phagocytic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Phagocytic vesicle - macrophage-specific.
    action: KEEP_AS_NON_CORE
    reason: Phagocytic vesicle - macrophage-specific.
- term:
    id: GO:0048513
    label: animal organ development
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Animal organ development is very broad.
    action: MARK_AS_OVER_ANNOTATED
    reason: Animal organ development is very broad.
- term:
    id: GO:0050804
    label: modulation of chemical synaptic transmission
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Modulation of chemical synaptic transmission - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Modulation of chemical synaptic transmission - tissue-specific.
- term:
    id: GO:0051239
    label: regulation of multicellular organismal process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of multicellular organismal process - very broad.
    action: KEEP_AS_NON_CORE
    reason: Regulation of multicellular organismal process - very broad.
- term:
    id: GO:0051247
    label: positive regulation of protein metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Positive regulation of protein metabolic process - broad.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of protein metabolic process - broad.
- term:
    id: GO:0060627
    label: regulation of vesicle-mediated transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of vesicle-mediated transport - core trafficking function.
    action: ACCEPT
    reason: Regulation of vesicle-mediated transport - core trafficking function.
- term:
    id: GO:0070013
    label: intracellular organelle lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Intracellular organelle lumen - very broad.
    action: KEEP_AS_NON_CORE
    reason: Intracellular organelle lumen - very broad.
- term:
    id: GO:0106310
    label: protein serine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  review:
    summary: Protein serine kinase activity - LRRK2 phosphorylates serine/threonine residues on Rab substrates.
    action: ACCEPT
    reason: Protein serine kinase activity - LRRK2 phosphorylates serine/threonine residues on Rab substrates.
- term:
    id: GO:1902531
    label: regulation of intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Regulation of intracellular signal transduction - broad.
    action: KEEP_AS_NON_CORE
    reason: Regulation of intracellular signal transduction - broad.
- term:
    id: GO:1904887
    label: Wnt signalosome assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Wnt signalosome assembly - via LRP6 bridging.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome assembly - via LRP6 bridging.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16321986
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16352719
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:16352719
      supporting_text: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17400507
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:17400507
      supporting_text: Identification of potential protein interactors of Lrrk2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18367605
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:18367605
      supporting_text: The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18445495
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:18445495
      supporting_text: Epub 2008 Mar 5. LRRK2 regulates synaptic vesicle endocytosis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19176810
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:19176810
      supporting_text: The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19196961
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:19196961
      supporting_text: CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19559761
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:19559761
      supporting_text: Interaction of elongation factor 1-alpha with leucine-rich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19625296
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:19625296
      supporting_text: Jul 22. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19712061
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:19712061
      supporting_text: 'Epub 2009 Aug 27. Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20067578
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:20067578
      supporting_text: Epub 2010 Jan 7. MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20144646
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:20144646
      supporting_text: '2010 Feb 6. Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20173330
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:20173330
      supporting_text: 'LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20642453
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:20642453
      supporting_text: 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20671708
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:20671708
      supporting_text: Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21048939
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21307259
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21307259
      supporting_text: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21370995
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21454543
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21454543
      supporting_text: 2011 Mar 16. Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21658387
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21658387
      supporting_text: "Epub 2011 Jun 2. LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson's disease-associated mutations."
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21850687
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21983832
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21983832
      supporting_text: The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22228096
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22228096
      supporting_text: Jan 6. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22303461
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22303461
      supporting_text: 'LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22363216
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22363216
      supporting_text: Feb 9. GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22612223
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22612223
      supporting_text: The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22639965
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22639965
      supporting_text: Epub 2012 Jun 22. Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22899650
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22952686
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22952686
      supporting_text: Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22998870
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:22998870
      supporting_text: LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23075850
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23075850
      supporting_text: Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23183827
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23183827
      supporting_text: 2012 Nov 27. LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23241358
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23241358
      supporting_text: Dec 13. GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23395371
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23395371
      supporting_text: RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23455607
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23455607
      supporting_text: Interplay of LRRK2 with chaperone-mediated autophagy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23813973
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23813973
      supporting_text: Jun 27. Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23937259
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23937259
      supporting_text: Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23949442
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:23949442
      supporting_text: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24113872
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24113872
      supporting_text: 2013 Oct 11. LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24165324
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24165324
      supporting_text: Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3β.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24275654
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24275654
      supporting_text: 2013 Nov 25. A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24282027
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24282027
      supporting_text: Nov 26. Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24351927
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24351927
      supporting_text: Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24459295
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24459295
      supporting_text: Jan 23. Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24464040
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24464040
      supporting_text: LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24510904
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24510904
      supporting_text: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24687852
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24687852
      supporting_text: Mar 31. Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24695735
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24695735
      supporting_text: 2014 Apr 2. The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24725412
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24725412
      supporting_text: Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24754922
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24754922
      supporting_text: MAP1B rescues LRRK2 mutant-mediated cytotoxicity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24794857
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24794857
      supporting_text: May 2. A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24904275
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24904275
      supporting_text: eCollection 2014. LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24947832
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:24947832
      supporting_text: Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25009464
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25009464
      supporting_text: eCollection 2014. LRRK2 kinase activity and biology are not uniformly predicted by its autophosphorylation and cellular phosphorylation site status.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25201882
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25201882
      supporting_text: Sep 8. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25360523
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25360523
      supporting_text: eCollection 2014. LRRK2 transport is regulated by its novel interacting partner Rab32.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25446991
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25446991
      supporting_text: Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25500533
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25500533
      supporting_text: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25501810
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25501810
      supporting_text: LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25605758
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:25605758
      supporting_text: An early endosome regulator, Rab5b, is an LRRK2 kinase substrate.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26824392
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:26824392
      supporting_text: Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26894577
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:26894577
      supporting_text: Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27013965
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:27013965
      supporting_text: eCollection 2016. Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27273569
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:27273569
      supporting_text: Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27314038
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:27314038
      supporting_text: G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27357661
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:27357661
      supporting_text: Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27424887
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:27424887
      supporting_text: LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28202711
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:28202711
      supporting_text: Structural interface between LRRK2 and 14-3-3 protein.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29513927
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:29513927
      supporting_text: Apr 17. Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29519959
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:29519959
      supporting_text: P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29541021
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:29541021
      supporting_text: eCollection 2018. The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31046837
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:31046837
      supporting_text: Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31552791
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:31552791
      supporting_text: Epub 2019 Sep 25. LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32017888
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:32017888
      supporting_text: 2020 Feb 3. Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33938021
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:33938021
      supporting_text: Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16321986
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18230735
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:18230735
      supporting_text: Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:18397888
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:18397888
      supporting_text: 2008 Apr 8. The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19712061
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:19712061
      supporting_text: 'Epub 2009 Aug 27. Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:19733152
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:19733152
      supporting_text: The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:20515039
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:20515039
      supporting_text: Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21073465
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:21073465
      supporting_text: Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22363216
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:22363216
      supporting_text: Feb 9. GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22952686
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:22952686
      supporting_text: Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23220480
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:23220480
      supporting_text: "Dominant-negative effects of LRRK2 heterodimers: a possible mechanism of neurodegeneration in Parkinson's disease caused by LRRK2 I2020T mutation."
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:23241358
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:23241358
      supporting_text: Dec 13. GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24275654
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:24275654
      supporting_text: 2013 Nov 25. A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24591621
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:24591621
      supporting_text: Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24904275
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:24904275
      supporting_text: eCollection 2014. LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:26824392
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:26824392
      supporting_text: Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:27013965
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:27013965
      supporting_text: eCollection 2016. Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:27357661
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:27357661
      supporting_text: Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cytoplasm is a major localization for LRRK2.
    action: ACCEPT
    reason: Cytoplasm is a major localization for LRRK2.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Mitochondrial inner membrane - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial inner membrane - reported but may be minor.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Mitochondrial matrix - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial matrix - reported but may be minor.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Endoplasmic reticulum - documented localization at ER exit sites.
    action: ACCEPT
    reason: Endoplasmic reticulum - documented localization at ER exit sites.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
    action: ACCEPT
    reason: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Trans-Golgi network localization is supported by Rab29-mediated recruitment studies.
    action: ACCEPT
    reason: Trans-Golgi network localization is supported by Rab29-mediated recruitment studies.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
- term:
    id: GO:0007029
    label: endoplasmic reticulum organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
    action: ACCEPT
    reason: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
- term:
    id: GO:0007283
    label: spermatogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Spermatogenesis is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Spermatogenesis is tissue-specific.
- term:
    id: GO:0008021
    label: synaptic vesicle
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Synaptic vesicle is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Synaptic vesicle is tissue-specific in neurons.
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Intracellular protein localization - broad but relevant to trafficking role.
    action: ACCEPT
    reason: Intracellular protein localization - broad but relevant to trafficking role.
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
- term:
    id: GO:0010977
    label: negative regulation of neuron projection development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of neuron projection development - neuronal.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of neuron projection development - neuronal.
- term:
    id: GO:0021756
    label: striatum development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Striatum development is tissue-specific developmental effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Striatum development is tissue-specific developmental effect.
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Small GTPase binding - LRRK2 binds Rab substrates and other small GTPases.
    action: ACCEPT
    reason: Small GTPase binding - LRRK2 binds Rab substrates and other small GTPases.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of proteasomal ubiquitin-dependent protein catabolic process - downstream.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of proteasomal ubiquitin-dependent protein catabolic process - downstream.
- term:
    id: GO:0032760
    label: positive regulation of tumor necrosis factor production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of TNF production is downstream immune effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of TNF production is downstream immune effect.
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Intracellular signal transduction - LRRK2 functions as a kinase that phosphorylates Rab GTPases.
    action: ACCEPT
    reason: Intracellular signal transduction - LRRK2 functions as a kinase that phosphorylates Rab GTPases.
- term:
    id: GO:0035564
    label: regulation of kidney size
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of kidney size is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of kidney size is tissue-specific.
- term:
    id: GO:0035641
    label: locomotory exploration behavior
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Locomotory exploration behavior is organismal phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: Locomotory exploration behavior is organismal phenotype.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Neuronal cell body is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal cell body is tissue-specific localization.
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Membrane raft - reported localization.
    action: KEEP_AS_NON_CORE
    reason: Membrane raft - reported localization.
- term:
    id: GO:0045202
    label: synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Synapse is tissue-specific neuronal localization.
    action: KEEP_AS_NON_CORE
    reason: Synapse is tissue-specific neuronal localization.
- term:
    id: GO:0051018
    label: protein kinase A binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Protein kinase A binding - interaction documented but not core.
    action: KEEP_AS_NON_CORE
    reason: Protein kinase A binding - interaction documented but not core.
- term:
    id: GO:0051966
    label: regulation of synaptic transmission, glutamatergic
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of synaptic transmission, glutamatergic - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic transmission, glutamatergic - tissue-specific.
- term:
    id: GO:0060079
    label: excitatory postsynaptic potential
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Excitatory postsynaptic potential - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Excitatory postsynaptic potential - tissue-specific.
- term:
    id: GO:0060159
    label: regulation of dopamine receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulation of dopamine receptor signaling pathway - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dopamine receptor signaling pathway - tissue-specific.
- term:
    id: GO:0060628
    label: regulation of ER to Golgi vesicle-mediated transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of ER to Golgi vesicle-mediated transport - via Sec16A regulation.
    action: ACCEPT
    reason: Regulation of ER to Golgi vesicle-mediated transport - via Sec16A regulation.
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
    action: KEEP_AS_NON_CORE
    reason: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
- term:
    id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Regulation of dendritic spine morphogenesis - neuronal effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dendritic spine morphogenesis - neuronal effect.
- term:
    id: GO:0070971
    label: endoplasmic reticulum exit site
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: ER exit site localization - LRRK2 regulates Sec16A at ER exit sites.
    action: ACCEPT
    reason: ER exit site localization - LRRK2 regulates Sec16A at ER exit sites.
- term:
    id: GO:0070973
    label: protein localization to endoplasmic reticulum exit site
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Protein localization to ER exit site - LRRK2 regulates Sec16A.
    action: ACCEPT
    reason: Protein localization to ER exit site - LRRK2 regulates Sec16A.
- term:
    id: GO:0090394
    label: negative regulation of excitatory postsynaptic potential
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Negative regulation of excitatory postsynaptic potential - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of excitatory postsynaptic potential - tissue-specific.
- term:
    id: GO:0098978
    label: glutamatergic synapse
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Glutamatergic synapse is tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Glutamatergic synapse is tissue-specific.
- term:
    id: GO:0099523
    label: presynaptic cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Presynaptic cytosol is tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Presynaptic cytosol is tissue-specific.
- term:
    id: GO:0140058
    label: neuron projection arborization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Neuron projection arborization is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Neuron projection arborization is developmental.
- term:
    id: GO:0141161
    label: regulation of cAMP/PKA signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of cAMP/PKA signal transduction - related to dopamine signaling.
    action: KEEP_AS_NON_CORE
    reason: Regulation of cAMP/PKA signal transduction - related to dopamine signaling.
- term:
    id: GO:1900242
    label: regulation of synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of synaptic vesicle endocytosis - well-documented LRRK2 function.
    action: ACCEPT
    reason: Regulation of synaptic vesicle endocytosis - well-documented LRRK2 function.
- term:
    id: GO:1900244
    label: positive regulation of synaptic vesicle endocytosis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of synaptic vesicle endocytosis - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of synaptic vesicle endocytosis - tissue-specific.
- term:
    id: GO:1902803
    label: regulation of synaptic vesicle transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Regulation of synaptic vesicle transport - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic vesicle transport - tissue-specific.
- term:
    id: GO:1903980
    label: positive regulation of microglial cell activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Positive regulation of microglial cell activation is downstream immune effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of microglial cell activation is downstream immune effect.
- term:
    id: GO:1904644
    label: cellular response to curcumin
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Cellular response to curcumin is an experimental condition response.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to curcumin is an experimental condition response.
- term:
    id: GO:1904713
    label: beta-catenin destruction complex binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Beta-catenin destruction complex binding - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Beta-catenin destruction complex binding - scaffold role.
- term:
    id: GO:1990904
    label: ribonucleoprotein complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Ribonucleoprotein complex - specific interaction.
    action: KEEP_AS_NON_CORE
    reason: Ribonucleoprotein complex - specific interaction.
- term:
    id: GO:1990909
    label: Wnt signalosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Wnt signalosome localization - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome localization - scaffold role.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:26751287
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:26751287
      supporting_text: The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
- term:
    id: GO:1905504
    label: negative regulation of motile cilium assembly
  evidence_type: TAS
  original_reference_id: PMID:30398148
  review:
    summary: Negative regulation of motile cilium assembly - core function via Rab8/Rab10/RILPL1 axis.
    action: ACCEPT
    reason: Negative regulation of motile cilium assembly - core function via Rab8/Rab10/RILPL1 axis.
    supported_by:
    - reference_id: PMID:30398148
      supporting_text: A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.
- term:
    id: GO:0035542
    label: regulation of SNARE complex assembly
  evidence_type: IMP
  original_reference_id: PMID:23949442
  review:
    summary: Regulation of SNARE complex assembly - related to vesicle function.
    action: KEEP_AS_NON_CORE
    reason: Regulation of SNARE complex assembly - related to vesicle function.
    supported_by:
    - reference_id: PMID:23949442
      supporting_text: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:21857923
  review:
    summary: Positive regulation of MAPK cascade - may be indirect.
    action: UNDECIDED
    reason: Positive regulation of MAPK cascade - may be indirect.
    supported_by:
    - reference_id: PMID:21857923
      supporting_text: Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C.
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:23628791
  review:
    summary: Positive regulation of MAPK cascade - may be indirect.
    action: UNDECIDED
    reason: Positive regulation of MAPK cascade - may be indirect.
    supported_by:
    - reference_id: PMID:23628791
      supporting_text: 2013 Apr 27. Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.
- term:
    id: GO:1901030
    label: positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:21370995
  review:
    summary: Positive regulation of mitochondrial outer membrane permeabilization in apoptotic signaling is disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of mitochondrial outer membrane permeabilization in apoptotic signaling is disease-related.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:38127736
  review:
    summary: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    action: ACCEPT
    reason: Identical protein binding - LRRK2 forms homodimers, important for regulation.
    supported_by:
    - reference_id: PMID:38127736
      supporting_text: 2023 Dec 21. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:38858457
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:38858457
      supporting_text: 2024 Jun 10. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.
- term:
    id: GO:0141161
    label: regulation of cAMP/PKA signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of cAMP/PKA signal transduction - related to dopamine signaling.
    action: KEEP_AS_NON_CORE
    reason: Regulation of cAMP/PKA signal transduction - related to dopamine signaling.
- term:
    id: GO:0007266
    label: Rho protein signal transduction
  evidence_type: IDA
  original_reference_id: PMID:25500533
  review:
    summary: Rho protein signal transduction - may be downstream effect.
    action: UNDECIDED
    reason: Rho protein signal transduction - may be downstream effect.
    supported_by:
    - reference_id: PMID:25500533
      supporting_text: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.
- term:
    id: GO:0034614
    label: cellular response to reactive oxygen species
  evidence_type: IMP
  original_reference_id: PMID:24576675
  review:
    summary: Cellular response to reactive oxygen species is disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to reactive oxygen species is disease-related.
    supported_by:
    - reference_id: PMID:24576675
      supporting_text: LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.
- term:
    id: GO:2000377
    label: regulation of reactive oxygen species metabolic process
  evidence_type: IMP
  original_reference_id: PMID:24576675
  review:
    summary: Regulation of ROS metabolic process is downstream.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of ROS metabolic process is downstream.
    supported_by:
    - reference_id: PMID:24576675
      supporting_text: LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:27830463
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:27830463
      supporting_text: Nov 9. LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation.
- term:
    id: GO:0030159
    label: signaling receptor complex adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:22899650
  review:
    summary: Signaling receptor complex adaptor activity - Wnt scaffold role.
    action: UNDECIDED
    reason: Signaling receptor complex adaptor activity - Wnt scaffold role.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0039706
    label: co-receptor binding
  evidence_type: TAS
  original_reference_id: PMID:24115276
  review:
    summary: Co-receptor binding - Wnt-related, needs verification.
    action: UNDECIDED
    reason: Co-receptor binding - Wnt-related, needs verification.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:0090263
    label: positive regulation of canonical Wnt signaling pathway
  evidence_type: IGI
  original_reference_id: PMID:22899650
  review:
    summary: Positive regulation of canonical Wnt signaling pathway - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of canonical Wnt signaling pathway - scaffold role.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0097413
    label: Lewy body
  evidence_type: IDA
  original_reference_id: PMID:27273569
  review:
    summary: Lewy body - disease-specific pathological structure.
    action: KEEP_AS_NON_CORE
    reason: Lewy body - disease-specific pathological structure.
    supported_by:
    - reference_id: PMID:27273569
      supporting_text: Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
- term:
    id: GO:0004706
    label: JUN kinase kinase kinase activity
  evidence_type: IDA
  original_reference_id: PMID:19302196
  review:
    summary: JUN kinase kinase kinase activity - reported but may not be physiological core function.
    action: UNDECIDED
    reason: JUN kinase kinase kinase activity - reported but may not be physiological core function.
    supported_by:
    - reference_id: PMID:19302196
      supporting_text: Epub 2009 Mar 3. The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.
- term:
    id: GO:0004709
    label: MAP kinase kinase kinase activity
  evidence_type: IDA
  original_reference_id: PMID:19302196
  review:
    summary: MAP kinase kinase kinase activity - reported in vitro but physiological relevance unclear.
    action: UNDECIDED
    reason: MAP kinase kinase kinase activity - reported in vitro but physiological relevance unclear.
    supported_by:
    - reference_id: PMID:19302196
      supporting_text: Epub 2009 Mar 3. The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.
- term:
    id: GO:0007254
    label: JNK cascade
  evidence_type: IDA
  original_reference_id: PMID:19302196
  review:
    summary: JNK cascade - reported but physiological relevance as direct function unclear.
    action: UNDECIDED
    reason: JNK cascade - reported but physiological relevance as direct function unclear.
    supported_by:
    - reference_id: PMID:19302196
      supporting_text: Epub 2009 Mar 3. The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.
- term:
    id: GO:0000287
    label: magnesium ion binding
  evidence_type: IMP
  original_reference_id: PMID:28720718
  review:
    summary: GO term GO:0000287 requires further review - no pre-defined decision available.
    action: UNDECIDED
    reason: Term not in curated decision list, requires manual review.
    supported_by:
    - reference_id: PMID:28720718
      supporting_text: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IMP
  original_reference_id: PMID:28720718
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:28720718
      supporting_text: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26014385
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:26014385
      supporting_text: 2015 May 27. LRRK2 Promotes Tau Accumulation, Aggregation and Release.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28720718
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:28720718
      supporting_text: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IMP
  original_reference_id: PMID:26014385
  review:
    summary: Cytoplasm is a major localization for LRRK2.
    action: ACCEPT
    reason: Cytoplasm is a major localization for LRRK2.
    supported_by:
    - reference_id: PMID:26014385
      supporting_text: 2015 May 27. LRRK2 Promotes Tau Accumulation, Aggregation and Release.
- term:
    id: GO:0006468
    label: protein phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:28720718
  review:
    summary: Protein phosphorylation - core enzymatic function of LRRK2 kinase domain.
    action: ACCEPT
    reason: Protein phosphorylation - core enzymatic function of LRRK2 kinase domain.
    supported_by:
    - reference_id: PMID:28720718
      supporting_text: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
- term:
    id: GO:0031647
    label: regulation of protein stability
  evidence_type: IMP
  original_reference_id: PMID:26014385
  review:
    summary: Regulation of protein stability - tau-related.
    action: KEEP_AS_NON_CORE
    reason: Regulation of protein stability - tau-related.
    supported_by:
    - reference_id: PMID:26014385
      supporting_text: 2015 May 27. LRRK2 Promotes Tau Accumulation, Aggregation and Release.
- term:
    id: GO:0007029
    label: endoplasmic reticulum organization
  evidence_type: IMP
  original_reference_id: PMID:25201882
  review:
    summary: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
    action: ACCEPT
    reason: ER organization is related to LRRK2 role in Sec16A regulation at ER exit sites.
    supported_by:
    - reference_id: PMID:25201882
      supporting_text: Sep 8. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
- term:
    id: GO:0060628
    label: regulation of ER to Golgi vesicle-mediated transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of ER to Golgi vesicle-mediated transport - via Sec16A regulation.
    action: ACCEPT
    reason: Regulation of ER to Golgi vesicle-mediated transport - via Sec16A regulation.
- term:
    id: GO:0070971
    label: endoplasmic reticulum exit site
  evidence_type: IDA
  original_reference_id: PMID:25201882
  review:
    summary: ER exit site localization - LRRK2 regulates Sec16A at ER exit sites.
    action: ACCEPT
    reason: ER exit site localization - LRRK2 regulates Sec16A at ER exit sites.
    supported_by:
    - reference_id: PMID:25201882
      supporting_text: Sep 8. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
- term:
    id: GO:0070973
    label: protein localization to endoplasmic reticulum exit site
  evidence_type: IMP
  original_reference_id: PMID:25201882
  review:
    summary: Protein localization to ER exit site - LRRK2 regulates Sec16A.
    action: ACCEPT
    reason: Protein localization to ER exit site - LRRK2 regulates Sec16A.
    supported_by:
    - reference_id: PMID:25201882
      supporting_text: Sep 8. Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
- term:
    id: GO:0099400
    label: caveola neck
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Caveola neck - specific localization.
    action: KEEP_AS_NON_CORE
    reason: Caveola neck - specific localization.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:1905289
    label: regulation of CAMKK-AMPK signaling cascade
  evidence_type: IMP
  original_reference_id: PMID:22012985
  review:
    summary: Regulation of CAMKK-AMPK signaling cascade - downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of CAMKK-AMPK signaling cascade - downstream effect.
    supported_by:
    - reference_id: PMID:22012985
      supporting_text: Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:23395371
  review:
    summary: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
    action: ACCEPT
    reason: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
    supported_by:
    - reference_id: PMID:23395371
      supporting_text: RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
- term:
    id: GO:1905279
    label: regulation of retrograde transport, endosome to Golgi
  evidence_type: IGI
  original_reference_id: PMID:23395371
  review:
    summary: Regulation of retrograde transport, endosome to Golgi - via Rab29/RAB7L1 interaction.
    action: ACCEPT
    reason: Regulation of retrograde transport, endosome to Golgi - via Rab29/RAB7L1 interaction.
    supported_by:
    - reference_id: PMID:23395371
      supporting_text: RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
- term:
    id: GO:0060828
    label: regulation of canonical Wnt signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:22988876
  review:
    summary: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
    action: KEEP_AS_NON_CORE
    reason: Regulation of canonical Wnt signaling pathway - LRRK2 acts as scaffold but not core function.
    supported_by:
    - reference_id: PMID:22988876
      supporting_text: The importance of Wnt signalling for neurodegeneration in Parkinson's disease.
- term:
    id: GO:0008017
    label: microtubule binding
  evidence_type: TAS
  original_reference_id: PMID:24115276
  review:
    summary: Microtubule binding - documented but significance unclear.
    action: KEEP_AS_NON_CORE
    reason: Microtubule binding - documented but significance unclear.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:0060070
    label: canonical Wnt signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:24115276
  review:
    summary: Canonical Wnt signaling pathway - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Canonical Wnt signaling pathway - scaffold role.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:1904713
    label: beta-catenin destruction complex binding
  evidence_type: NAS
  original_reference_id: PMID:24115276
  review:
    summary: Beta-catenin destruction complex binding - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Beta-catenin destruction complex binding - scaffold role.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:1904887
    label: Wnt signalosome assembly
  evidence_type: TAS
  original_reference_id: PMID:24115276
  review:
    summary: Wnt signalosome assembly - via LRP6 bridging.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome assembly - via LRP6 bridging.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:1990909
    label: Wnt signalosome
  evidence_type: NAS
  original_reference_id: PMID:24115276
  review:
    summary: Wnt signalosome localization - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome localization - scaffold role.
    supported_by:
    - reference_id: PMID:24115276
      supporting_text: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
- term:
    id: GO:1904887
    label: Wnt signalosome assembly
  evidence_type: IPI
  original_reference_id: PMID:22899650
  review:
    summary: Wnt signalosome assembly - via LRP6 bridging.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome assembly - via LRP6 bridging.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0035751
    label: regulation of lysosomal lumen pH
  evidence_type: IMP
  original_reference_id: PMID:22012985
  review:
    summary: Regulation of lysosomal lumen pH - via effects on lysosomal function.
    action: ACCEPT
    reason: Regulation of lysosomal lumen pH - via effects on lysosomal function.
    supported_by:
    - reference_id: PMID:22012985
      supporting_text: Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
- term:
    id: GO:1990909
    label: Wnt signalosome
  evidence_type: IDA
  original_reference_id: PMID:22899650
  review:
    summary: Wnt signalosome localization - scaffold role.
    action: KEEP_AS_NON_CORE
    reason: Wnt signalosome localization - scaffold role.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Endoplasmic reticulum - documented localization at ER exit sites.
    action: ACCEPT
    reason: Endoplasmic reticulum - documented localization at ER exit sites.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0005902
    label: microvillus
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Microvillus - specific localization.
    action: KEEP_AS_NON_CORE
    reason: Microvillus - specific localization.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0016242
    label: negative regulation of macroautophagy
  evidence_type: IMP
  original_reference_id: PMID:19640926
  review:
    summary: Negative regulation of macroautophagy is downstream of trafficking effects.
    action: MARK_AS_OVER_ANNOTATED
    reason: Negative regulation of macroautophagy is downstream of trafficking effects.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0044753
    label: amphisome
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Amphisome - autophagy-related.
    action: KEEP_AS_NON_CORE
    reason: Amphisome - autophagy-related.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0044754
    label: autolysosome
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Autolysosome - autophagy-related.
    action: KEEP_AS_NON_CORE
    reason: Autolysosome - autophagy-related.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0097487
    label: multivesicular body, internal vesicle
  evidence_type: IDA
  original_reference_id: PMID:19640926
  review:
    summary: Multivesicular body, internal vesicle - endosomal.
    action: KEEP_AS_NON_CORE
    reason: Multivesicular body, internal vesicle - endosomal.
    supported_by:
    - reference_id: PMID:19640926
      supporting_text: Jul 29. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:22899650
  review:
    summary: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
    action: KEEP_AS_NON_CORE
    reason: Plasma membrane - LRRK2 can localize to membranes but cytosol is predominant.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IMP
  original_reference_id: PMID:23916833
  review:
    summary: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
    action: ACCEPT
    reason: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
    supported_by:
    - reference_id: PMID:23916833
      supporting_text: Inhibition of LRRK2 kinase activity stimulates macroautophagy.
- term:
    id: GO:1902902
    label: negative regulation of autophagosome assembly
  evidence_type: IMP
  original_reference_id: PMID:23916833
  review:
    summary: Negative regulation of autophagosome assembly is downstream effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Negative regulation of autophagosome assembly is downstream effect.
    supported_by:
    - reference_id: PMID:23916833
      supporting_text: Inhibition of LRRK2 kinase activity stimulates macroautophagy.
- term:
    id: GO:0009267
    label: cellular response to starvation
  evidence_type: IMP
  original_reference_id: PMID:24211199
  review:
    summary: Cellular response to starvation is experimental condition.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to starvation is experimental condition.
    supported_by:
    - reference_id: PMID:24211199
      supporting_text: Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation.
- term:
    id: GO:0010506
    label: regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:24211199
  review:
    summary: Regulation of autophagy is downstream of trafficking/lysosomal effects.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of autophagy is downstream of trafficking/lysosomal effects.
    supported_by:
    - reference_id: PMID:24211199
      supporting_text: Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:22899650
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: TAS
  original_reference_id: PMID:22899650
  review:
    summary: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    action: ACCEPT
    reason: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:22899650
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    supported_by:
    - reference_id: PMID:22899650
      supporting_text: Aug 16. LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:25500533
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    supported_by:
    - reference_id: PMID:25500533
      supporting_text: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.
- term:
    id: GO:0005798
    label: Golgi-associated vesicle
  evidence_type: IDA
  original_reference_id: PMID:24510904
  review:
    summary: Golgi-associated vesicle - consistent with trafficking role.
    action: ACCEPT
    reason: Golgi-associated vesicle - consistent with trafficking role.
    supported_by:
    - reference_id: PMID:24510904
      supporting_text: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.
- term:
    id: GO:0007030
    label: Golgi organization
  evidence_type: IMP
  original_reference_id: PMID:24510904
  review:
    summary: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
    action: ACCEPT
    reason: Golgi organization - LRRK2 regulates Golgi-related trafficking through Rab phosphorylation.
    supported_by:
    - reference_id: PMID:24510904
      supporting_text: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:19625296
  review:
    summary: Cytoplasm is a major localization for LRRK2.
    action: ACCEPT
    reason: Cytoplasm is a major localization for LRRK2.
    supported_by:
    - reference_id: PMID:19625296
      supporting_text: Jul 22. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.
- term:
    id: GO:0030426
    label: growth cone
  evidence_type: IDA
  original_reference_id: PMID:19625296
  review:
    summary: Growth cone is tissue-specific neuronal structure.
    action: KEEP_AS_NON_CORE
    reason: Growth cone is tissue-specific neuronal structure.
    supported_by:
    - reference_id: PMID:19625296
      supporting_text: Jul 22. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IDA
  original_reference_id: PMID:19625296
  review:
    summary: Neuron projection is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Neuron projection is tissue-specific in neurons.
    supported_by:
    - reference_id: PMID:19625296
      supporting_text: Jul 22. Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.
- term:
    id: GO:0090394
    label: negative regulation of excitatory postsynaptic potential
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Negative regulation of excitatory postsynaptic potential - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of excitatory postsynaptic potential - tissue-specific.
- term:
    id: GO:0007040
    label: lysosome organization
  evidence_type: IMP
  original_reference_id: PMID:25416817
  review:
    summary: Lysosome organization - consistent with endolysosomal trafficking role.
    action: ACCEPT
    reason: Lysosome organization - consistent with endolysosomal trafficking role.
    supported_by:
    - reference_id: PMID:25416817
      supporting_text: Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.
- term:
    id: GO:0019722
    label: calcium-mediated signaling
  evidence_type: IMP
  original_reference_id: PMID:25416817
  review:
    summary: Calcium-mediated signaling - via NAADP pathway.
    action: KEEP_AS_NON_CORE
    reason: Calcium-mediated signaling - via NAADP pathway.
    supported_by:
    - reference_id: PMID:25416817
      supporting_text: Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.
- term:
    id: GO:0046039
    label: GTP metabolic process
  evidence_type: IDA
  original_reference_id: PMID:21048939
  review:
    summary: GTP metabolic process - related to GTPase activity.
    action: ACCEPT
    reason: GTP metabolic process - related to GTPase activity.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0007005
    label: mitochondrion organization
  evidence_type: IMP
  original_reference_id: PMID:22764206
  review:
    summary: Mitochondrion organization effects are likely secondary.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mitochondrion organization effects are likely secondary.
    supported_by:
    - reference_id: PMID:22764206
      supporting_text: Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:22764206
  review:
    summary: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    supported_by:
    - reference_id: PMID:22764206
      supporting_text: Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.
- term:
    id: GO:0051646
    label: mitochondrion localization
  evidence_type: IMP
  original_reference_id: PMID:22764206
  review:
    summary: Mitochondrion localization effects are secondary.
    action: MARK_AS_OVER_ANNOTATED
    reason: Mitochondrion localization effects are secondary.
    supported_by:
    - reference_id: PMID:22764206
      supporting_text: Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8857565
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8857577
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8857583
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9634702
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:21857923
  review:
    summary: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    supported_by:
    - reference_id: PMID:21857923
      supporting_text: Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C.
- term:
    id: GO:1902236
    label: negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21857923
  review:
    summary: Negative regulation of ER stress-induced intrinsic apoptotic signaling pathway is disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Negative regulation of ER stress-induced intrinsic apoptotic signaling pathway is disease-related.
    supported_by:
    - reference_id: PMID:21857923
      supporting_text: Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C.
- term:
    id: GO:0014041
    label: regulation of neuron maturation
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Regulation of neuron maturation is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of neuron maturation is developmental.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:0021772
    label: olfactory bulb development
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Olfactory bulb development is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Olfactory bulb development is tissue-specific.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:0022028
    label: tangential migration from the subventricular zone to the olfactory bulb
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Tangential migration from subventricular zone is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tangential migration from subventricular zone is developmental.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Regulation of dendritic spine morphogenesis - neuronal effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dendritic spine morphogenesis - neuronal effect.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:2000172
    label: regulation of branching morphogenesis of a nerve
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Regulation of branching morphogenesis of a nerve is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of branching morphogenesis of a nerve is developmental.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:0061001
    label: regulation of dendritic spine morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of dendritic spine morphogenesis - neuronal effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dendritic spine morphogenesis - neuronal effect.
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:24252804
  review:
    summary: Protein localization to mitochondrion is secondary.
    action: MARK_AS_OVER_ANNOTATED
    reason: Protein localization to mitochondrion is secondary.
    supported_by:
    - reference_id: PMID:24252804
      supporting_text: The role of oxidative stress in Parkinson's disease.
- term:
    id: GO:0090140
    label: regulation of mitochondrial fission
  evidence_type: TAS
  original_reference_id: PMID:24252804
  review:
    summary: Regulation of mitochondrial fission is secondary effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of mitochondrial fission is secondary effect.
    supported_by:
    - reference_id: PMID:24252804
      supporting_text: The role of oxidative stress in Parkinson's disease.
- term:
    id: GO:0043195
    label: terminal bouton
  evidence_type: TAS
  original_reference_id: PMID:21563316
  review:
    summary: Terminal bouton is tissue-specific neuronal localization.
    action: KEEP_AS_NON_CORE
    reason: Terminal bouton is tissue-specific neuronal localization.
    supported_by:
    - reference_id: PMID:21563316
      supporting_text: Synaptic vesicle trafficking and Parkinson's disease.
- term:
    id: GO:0071287
    label: cellular response to manganese ion
  evidence_type: IMP
  original_reference_id: PMID:23628791
  review:
    summary: Cellular response to manganese ion is experimental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to manganese ion is experimental.
    supported_by:
    - reference_id: PMID:23628791
      supporting_text: 2013 Apr 27. Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.
- term:
    id: GO:1902803
    label: regulation of synaptic vesicle transport
  evidence_type: TAS
  original_reference_id: PMID:21563316
  review:
    summary: Regulation of synaptic vesicle transport - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic vesicle transport - tissue-specific.
    supported_by:
    - reference_id: PMID:21563316
      supporting_text: Synaptic vesicle trafficking and Parkinson's disease.
- term:
    id: GO:1903351
    label: cellular response to dopamine
  evidence_type: IMP
  original_reference_id: PMID:23628791
  review:
    summary: Cellular response to dopamine is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to dopamine is tissue-specific.
    supported_by:
    - reference_id: PMID:23628791
      supporting_text: 2013 Apr 27. Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IMP
  original_reference_id: PMID:24576675
  review:
    summary: Endocytosis - related to synaptic vesicle endocytosis role.
    action: KEEP_AS_NON_CORE
    reason: Endocytosis - related to synaptic vesicle endocytosis role.
    supported_by:
    - reference_id: PMID:24576675
      supporting_text: LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.
- term:
    id: GO:0006897
    label: endocytosis
  evidence_type: IGI
  original_reference_id: PMID:24576675
  review:
    summary: Endocytosis - related to synaptic vesicle endocytosis role.
    action: KEEP_AS_NON_CORE
    reason: Endocytosis - related to synaptic vesicle endocytosis role.
    supported_by:
    - reference_id: PMID:24576675
      supporting_text: LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:21362567
  review:
    summary: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    action: MARK_AS_OVER_ANNOTATED
    reason: Cellular response to oxidative stress is a pleiotropic disease-related effect.
    supported_by:
    - reference_id: PMID:21362567
      supporting_text: LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
- term:
    id: GO:0036479
    label: peroxidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:21850687
  review:
    summary: Peroxidase inhibitor activity - reported but unclear if core function.
    action: UNDECIDED
    reason: Peroxidase inhibitor activity - reported but unclear if core function.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:1903748
    label: negative regulation of protein localization to mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:21370995
  review:
    summary: GO term GO:1903748 requires further review - no pre-defined decision available.
    action: UNDECIDED
    reason: Term not in curated decision list, requires manual review.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:1902499
    label: positive regulation of protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16352719
  review:
    summary: Positive regulation of protein autoubiquitination - parkin-related.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of protein autoubiquitination - parkin-related.
    supported_by:
    - reference_id: PMID:16352719
      supporting_text: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IPI
  original_reference_id: PMID:21370995
  review:
    summary: Transmembrane transporter binding - various interactions.
    action: KEEP_AS_NON_CORE
    reason: Transmembrane transporter binding - various interactions.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:0010955
    label: negative regulation of protein processing
  evidence_type: IDA
  original_reference_id: PMID:21370995
  review:
    summary: Negative regulation of protein processing - specific effect.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of protein processing - specific effect.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:1903748
    label: negative regulation of protein localization to mitochondrion
  evidence_type: IC
  original_reference_id: PMID:21370995
  review:
    summary: GO term GO:1903748 requires further review - no pre-defined decision available.
    action: UNDECIDED
    reason: Term not in curated decision list, requires manual review.
    supported_by:
    - reference_id: PMID:21370995
      supporting_text: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
- term:
    id: GO:0008104
    label: intracellular protein localization
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Intracellular protein localization - broad but relevant to trafficking role.
    action: ACCEPT
    reason: Intracellular protein localization - broad but relevant to trafficking role.
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:20173330
  review:
    summary: Positive regulation of protein ubiquitination - related to parkin interaction.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of protein ubiquitination - related to parkin interaction.
    supported_by:
    - reference_id: PMID:20173330
      supporting_text: 'LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.'
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Intracellular signal transduction - LRRK2 functions as a kinase that phosphorylates Rab GTPases.
    action: ACCEPT
    reason: Intracellular signal transduction - LRRK2 functions as a kinase that phosphorylates Rab GTPases.
- term:
    id: GO:0051966
    label: regulation of synaptic transmission, glutamatergic
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of synaptic transmission, glutamatergic - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic transmission, glutamatergic - tissue-specific.
- term:
    id: GO:0060079
    label: excitatory postsynaptic potential
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Excitatory postsynaptic potential - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Excitatory postsynaptic potential - tissue-specific.
- term:
    id: GO:0060159
    label: regulation of dopamine receptor signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of dopamine receptor signaling pathway - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of dopamine receptor signaling pathway - tissue-specific.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:21850687
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:21850687
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Mitochondrial outer membrane - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial outer membrane - reported but may be minor.
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Mitochondrial inner membrane - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial inner membrane - reported but may be minor.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Mitochondrial matrix - reported but may be minor.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial matrix - reported but may be minor.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Lysosome localization is consistent with LRRK2 role in endolysosomal trafficking.
    action: ACCEPT
    reason: Lysosome localization is consistent with LRRK2 role in endolysosomal trafficking.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Endosome localization is consistent with LRRK2 role in regulating Rab-dependent trafficking.
    action: ACCEPT
    reason: Endosome localization is consistent with LRRK2 role in regulating Rab-dependent trafficking.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Endoplasmic reticulum - documented localization at ER exit sites.
    action: ACCEPT
    reason: Endoplasmic reticulum - documented localization at ER exit sites.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
    action: ACCEPT
    reason: Golgi apparatus localization is supported - LRRK2 is recruited to Golgi by Rab29.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IDA
  original_reference_id: PMID:17120249
  review:
    summary: Axon localization is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Axon localization is tissue-specific in neurons.
    supported_by:
    - reference_id: PMID:17120249
      supporting_text: Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: IDA
  original_reference_id: PMID:17120249
  review:
    summary: Dendrite localization is tissue-specific in neurons, not a core localization.
    action: KEEP_AS_NON_CORE
    reason: Dendrite localization is tissue-specific in neurons, not a core localization.
    supported_by:
    - reference_id: PMID:17120249
      supporting_text: Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
- term:
    id: GO:0031410
    label: cytoplasmic vesicle
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Cytoplasmic vesicle - consistent with trafficking role.
    action: ACCEPT
    reason: Cytoplasmic vesicle - consistent with trafficking role.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: IDA
  original_reference_id: PMID:17120249
  review:
    summary: Perikaryon (neuronal cell body) is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Perikaryon (neuronal cell body) is tissue-specific localization.
    supported_by:
    - reference_id: PMID:17120249
      supporting_text: Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IDA
  original_reference_id: PMID:17114044
  review:
    summary: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
    action: ACCEPT
    reason: Kinase activity is a core function - LRRK2 is a dual-function kinase/GTPase.
    supported_by:
    - reference_id: PMID:17114044
      supporting_text: The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
- term:
    id: GO:0030424
    label: axon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Axon localization is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Axon localization is tissue-specific in neurons.
- term:
    id: GO:0030425
    label: dendrite
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Dendrite localization is tissue-specific in neurons, not a core localization.
    action: KEEP_AS_NON_CORE
    reason: Dendrite localization is tissue-specific in neurons, not a core localization.
- term:
    id: GO:0043204
    label: perikaryon
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Perikaryon (neuronal cell body) is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Perikaryon (neuronal cell body) is tissue-specific localization.
- term:
    id: GO:0048812
    label: neuron projection morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:17114044
  review:
    summary: Neuron projection morphogenesis is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Neuron projection morphogenesis is developmental.
    supported_by:
    - reference_id: PMID:17114044
      supporting_text: The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
- term:
    id: GO:0000149
    label: SNARE binding
  evidence_type: IPI
  original_reference_id: PMID:21307259
  review:
    summary: SNARE binding - related to vesicle function.
    action: KEEP_AS_NON_CORE
    reason: SNARE binding - related to vesicle function.
    supported_by:
    - reference_id: PMID:21307259
      supporting_text: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IPI
  original_reference_id: PMID:21307259
  review:
    summary: Actin binding - documented interaction.
    action: KEEP_AS_NON_CORE
    reason: Actin binding - documented interaction.
    supported_by:
    - reference_id: PMID:21307259
      supporting_text: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
- term:
    id: GO:0017075
    label: syntaxin-1 binding
  evidence_type: IPI
  original_reference_id: PMID:21307259
  review:
    summary: Syntaxin-1 binding - vesicle-related.
    action: KEEP_AS_NON_CORE
    reason: Syntaxin-1 binding - vesicle-related.
    supported_by:
    - reference_id: PMID:21307259
      supporting_text: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
- term:
    id: GO:0030276
    label: clathrin binding
  evidence_type: IPI
  original_reference_id: PMID:21307259
  review:
    summary: Clathrin binding - endocytosis-related.
    action: KEEP_AS_NON_CORE
    reason: Clathrin binding - endocytosis-related.
    supported_by:
    - reference_id: PMID:21307259
      supporting_text: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
- term:
    id: GO:1902803
    label: regulation of synaptic vesicle transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of synaptic vesicle transport - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic vesicle transport - tissue-specific.
- term:
    id: GO:1902823
    label: negative regulation of late endosome to lysosome transport
  evidence_type: TAS
  original_reference_id: PMID:23949442
  review:
    summary: Negative regulation of late endosome to lysosome transport - downstream effect.
    action: KEEP_AS_NON_CORE
    reason: Negative regulation of late endosome to lysosome transport - downstream effect.
    supported_by:
    - reference_id: PMID:23949442
      supporting_text: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:23949442
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:23949442
      supporting_text: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
- term:
    id: GO:2000300
    label: regulation of synaptic vesicle exocytosis
  evidence_type: IMP
  original_reference_id: PMID:23949442
  review:
    summary: Regulation of synaptic vesicle exocytosis - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Regulation of synaptic vesicle exocytosis - tissue-specific.
    supported_by:
    - reference_id: PMID:23949442
      supporting_text: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
- term:
    id: GO:0051900
    label: regulation of mitochondrial depolarization
  evidence_type: IMP
  original_reference_id: PMID:22736029
  review:
    summary: Regulation of mitochondrial depolarization is disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of mitochondrial depolarization is disease-related.
    supported_by:
    - reference_id: PMID:22736029
      supporting_text: Jun 26. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:24403142
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    supported_by:
    - reference_id: PMID:24403142
      supporting_text: Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies.
- term:
    id: GO:0051018
    label: protein kinase A binding
  evidence_type: IPI
  original_reference_id: PMID:24464040
  review:
    summary: Protein kinase A binding - interaction documented but not core.
    action: KEEP_AS_NON_CORE
    reason: Protein kinase A binding - interaction documented but not core.
    supported_by:
    - reference_id: PMID:24464040
      supporting_text: LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:22736029
  review:
    summary: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    action: ACCEPT
    reason: Cytosol is the predominant localization of LRRK2, from which it is recruited to membranes.
    supported_by:
    - reference_id: PMID:22736029
      supporting_text: Jun 26. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:22736029
  review:
    summary: Mitochondrial membrane - reported.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrial membrane - reported.
    supported_by:
    - reference_id: PMID:22736029
      supporting_text: Jun 26. G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.
- term:
    id: GO:1902692
    label: regulation of neuroblast proliferation
  evidence_type: IMP
  original_reference_id: PMID:21168496
  review:
    summary: Regulation of neuroblast proliferation is developmental.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of neuroblast proliferation is developmental.
    supported_by:
    - reference_id: PMID:21168496
      supporting_text: 2010 Dec 16. Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: HDA
  original_reference_id: PMID:22664934
  review:
    summary: Extracellular space - exosome secretion.
    action: KEEP_AS_NON_CORE
    reason: Extracellular space - exosome secretion.
    supported_by:
    - reference_id: PMID:22664934
      supporting_text: Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  review:
    summary: Extracellular exosome - secreted in exosomes.
    action: KEEP_AS_NON_CORE
    reason: Extracellular exosome - secreted in exosomes.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: 2008 Dec 3. Large-scale proteomics and phosphoproteomics of urinary exosomes.
- term:
    id: GO:0032839
    label: dendrite cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:21696411
  review:
    summary: Dendrite cytoplasm is tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Dendrite cytoplasm is tissue-specific.
    supported_by:
    - reference_id: PMID:21696411
      supporting_text: "LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study."
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:21696411
  review:
    summary: Neuronal cell body is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal cell body is tissue-specific localization.
    supported_by:
    - reference_id: PMID:21696411
      supporting_text: "LRRK2 expression in idiopathic and G2019S positive Parkinson's disease subjects: a morphological and quantitative study."
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:22423108
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:22423108
      supporting_text: 'ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2.'
- term:
    id: GO:0034260
    label: negative regulation of GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:22423108
  review:
    summary: Negative regulation of GTPase activity - needs verification.
    action: UNDECIDED
    reason: Negative regulation of GTPase activity - needs verification.
    supported_by:
    - reference_id: PMID:22423108
      supporting_text: 'ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2.'
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:22012985
  review:
    summary: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
    supported_by:
    - reference_id: PMID:22012985
      supporting_text: Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
- term:
    id: GO:0044325
    label: transmembrane transporter binding
  evidence_type: IPI
  original_reference_id: PMID:22012985
  review:
    summary: Transmembrane transporter binding - various interactions.
    action: KEEP_AS_NON_CORE
    reason: Transmembrane transporter binding - various interactions.
    supported_by:
    - reference_id: PMID:22012985
      supporting_text: Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
- term:
    id: GO:0003924
    label: GTPase activity
  evidence_type: IDA
  original_reference_id: PMID:21048939
  review:
    summary: GTPase activity is a core function of LRRK2 ROC domain. The ROC domain binds and hydrolyzes GTP.
    action: ACCEPT
    reason: GTPase activity is a core function of LRRK2 ROC domain. The ROC domain binds and hydrolyzes GTP.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:21048939
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:21048939
  review:
    summary: Small GTPase binding - LRRK2 binds Rab substrates and other small GTPases.
    action: ACCEPT
    reason: Small GTPase binding - LRRK2 binds Rab substrates and other small GTPases.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0043005
    label: neuron projection
  evidence_type: IDA
  original_reference_id: PMID:21048939
  review:
    summary: Neuron projection is tissue-specific in neurons.
    action: KEEP_AS_NON_CORE
    reason: Neuron projection is tissue-specific in neurons.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IDA
  original_reference_id: PMID:21048939
  review:
    summary: Neuronal cell body is tissue-specific localization.
    action: KEEP_AS_NON_CORE
    reason: Neuronal cell body is tissue-specific localization.
    supported_by:
    - reference_id: PMID:21048939
      supporting_text: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:21850687
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:21850687
  review:
    summary: Mitochondrion - reported but not primary localization.
    action: KEEP_AS_NON_CORE
    reason: Mitochondrion - reported but not primary localization.
    supported_by:
    - reference_id: PMID:21850687
      supporting_text: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
- term:
    id: GO:0035640
    label: exploration behavior
  evidence_type: IMP
  original_reference_id: PMID:20659558
  review:
    summary: Exploration behavior is a high-level organismal phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exploration behavior is a high-level organismal phenotype.
    supported_by:
    - reference_id: PMID:20659558
      supporting_text: 2010 Jul 24. Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.
- term:
    id: GO:0060161
    label: positive regulation of dopamine receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:20659558
  review:
    summary: Positive regulation of dopamine receptor signaling pathway - tissue-specific.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of dopamine receptor signaling pathway - tissue-specific.
    supported_by:
    - reference_id: PMID:20659558
      supporting_text: 2010 Jul 24. Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.
- term:
    id: GO:0010508
    label: positive regulation of autophagy
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of autophagy is a downstream effect of trafficking disruption, not core function.
- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Positive regulation of proteasomal ubiquitin-dependent protein catabolic process - downstream.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of proteasomal ubiquitin-dependent protein catabolic process - downstream.
- term:
    id: GO:0035564
    label: regulation of kidney size
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Regulation of kidney size is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of kidney size is tissue-specific.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21159966
  review:
    summary: Protein binding is uninformative - LRRK2 has many documented interactors.
    action: KEEP_AS_NON_CORE
    reason: Protein binding is uninformative - LRRK2 has many documented interactors.
    supported_by:
    - reference_id: PMID:21159966
      supporting_text: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
- term:
    id: GO:0015631
    label: tubulin binding
  evidence_type: IDA
  original_reference_id: PMID:21159966
  review:
    summary: Tubulin binding - documented but not core function.
    action: KEEP_AS_NON_CORE
    reason: Tubulin binding - documented but not core function.
    supported_by:
    - reference_id: PMID:21159966
      supporting_text: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
- term:
    id: GO:0042391
    label: regulation of membrane potential
  evidence_type: IMP
  original_reference_id: PMID:21159966
  review:
    summary: Regulation of membrane potential - neuronal effect.
    action: KEEP_AS_NON_CORE
    reason: Regulation of membrane potential - neuronal effect.
    supported_by:
    - reference_id: PMID:21159966
      supporting_text: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
- term:
    id: GO:0048312
    label: intracellular distribution of mitochondria
  evidence_type: IMP
  original_reference_id: PMID:21159966
  review:
    summary: Intracellular distribution of mitochondria is secondary.
    action: MARK_AS_OVER_ANNOTATED
    reason: Intracellular distribution of mitochondria is secondary.
    supported_by:
    - reference_id: PMID:21159966
      supporting_text: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
- term:
    id: GO:0007528
    label: neuromuscular junction development
  evidence_type: IMP
  original_reference_id: PMID:21159966
  review:
    summary: Neuromuscular junction development is tissue-specific.
    action: MARK_AS_OVER_ANNOTATED
    reason: Neuromuscular junction development is tissue-specific.
    supported_by:
    - reference_id: PMID:21159966
      supporting_text: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:17260967
  review:
    summary: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    action: ACCEPT
    reason: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    supported_by:
    - reference_id: PMID:17260967
      supporting_text: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.
- term:
    id: GO:0034211
    label: GTP-dependent protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:17260967
  review:
    summary: GTP-dependent protein kinase activity reflects the intramolecular regulation between ROC GTPase and kinase domains.
    action: ACCEPT
    reason: GTP-dependent protein kinase activity reflects the intramolecular regulation between ROC GTPase and kinase domains.
    supported_by:
    - reference_id: PMID:17260967
      supporting_text: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:19692353
  review:
    summary: Response to oxidative stress is pleiotropic/disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Response to oxidative stress is pleiotropic/disease-related.
    supported_by:
    - reference_id: PMID:19692353
      supporting_text: Aug 19. Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.
- term:
    id: GO:0008340
    label: determination of adult lifespan
  evidence_type: IMP
  original_reference_id: PMID:19692353
  review:
    summary: Determination of adult lifespan is pleiotropic.
    action: MARK_AS_OVER_ANNOTATED
    reason: Determination of adult lifespan is pleiotropic.
    supported_by:
    - reference_id: PMID:19692353
      supporting_text: Aug 19. Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.
- term:
    id: GO:0040012
    label: regulation of locomotion
  evidence_type: IMP
  original_reference_id: PMID:19692353
  review:
    summary: Regulation of locomotion is high-level organismal phenotype.
    action: MARK_AS_OVER_ANNOTATED
    reason: Regulation of locomotion is high-level organismal phenotype.
    supported_by:
    - reference_id: PMID:19692353
      supporting_text: Aug 19. Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:19576176
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:19576176
      supporting_text: 'Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.'
- term:
    id: GO:0034211
    label: GTP-dependent protein kinase activity
  evidence_type: IMP
  original_reference_id: PMID:17200152
  review:
    summary: GTP-dependent protein kinase activity reflects the intramolecular regulation between ROC GTPase and kinase domains.
    action: ACCEPT
    reason: GTP-dependent protein kinase activity reflects the intramolecular regulation between ROC GTPase and kinase domains.
    supported_by:
    - reference_id: PMID:17200152
      supporting_text: Jan 2. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
- term:
    id: GO:0000165
    label: MAPK cascade
  evidence_type: IDA
  original_reference_id: PMID:17200152
  review:
    summary: MAPK cascade - reported but may be downstream effect.
    action: UNDECIDED
    reason: MAPK cascade - reported but may be downstream effect.
    supported_by:
    - reference_id: PMID:17200152
      supporting_text: Jan 2. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16269541
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    supported_by:
    - reference_id: PMID:16269541
      supporting_text: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:17442267
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    supported_by:
    - reference_id: PMID:17442267
      supporting_text: The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
- term:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:17200152
  review:
    summary: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    action: ACCEPT
    reason: Protein serine/threonine kinase activity is a core enzymatic function of LRRK2. The kinase domain phosphorylates Rab GTPases at their switch II regions.
    supported_by:
    - reference_id: PMID:17200152
      supporting_text: Jan 2. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
- term:
    id: GO:0005096
    label: GTPase activator activity
  evidence_type: IDA
  original_reference_id: PMID:17442267
  review:
    summary: GTPase activator activity - LRRK2 has intrinsic GTPase activity but GAP activity on other GTPases is unclear.
    action: UNDECIDED
    reason: GTPase activator activity - LRRK2 has intrinsic GTPase activity but GAP activity on other GTPases is unclear.
    supported_by:
    - reference_id: PMID:17442267
      supporting_text: The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:16980962
  review:
    summary: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    action: ACCEPT
    reason: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    supported_by:
    - reference_id: PMID:16980962
      supporting_text: Kinase activity of mutant LRRK2 mediates neuronal toxicity.
- term:
    id: GO:0005525
    label: GTP binding
  evidence_type: IDA
  original_reference_id: PMID:17442267
  review:
    summary: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    action: ACCEPT
    reason: GTP binding is essential for LRRK2 ROC domain function and regulates kinase activity.
    supported_by:
    - reference_id: PMID:17442267
      supporting_text: The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
- term:
    id: GO:0032473
    label: cytoplasmic side of mitochondrial outer membrane
  evidence_type: IDA
  original_reference_id: PMID:16269541
  review:
    summary: Cytoplasmic side of mitochondrial outer membrane - reported.
    action: KEEP_AS_NON_CORE
    reason: Cytoplasmic side of mitochondrial outer membrane - reported.
    supported_by:
    - reference_id: PMID:16269541
      supporting_text: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
- term:
    id: GO:0043068
    label: positive regulation of programmed cell death
  evidence_type: IDA
  original_reference_id: PMID:17200152
  review:
    summary: Positive regulation of programmed cell death is disease-related.
    action: MARK_AS_OVER_ANNOTATED
    reason: Positive regulation of programmed cell death is disease-related.
    supported_by:
    - reference_id: PMID:17200152
      supporting_text: Jan 2. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:16269541
  review:
    summary: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    action: ACCEPT
    reason: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    supported_by:
    - reference_id: PMID:16269541
      supporting_text: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IMP
  original_reference_id: PMID:16980962
  review:
    summary: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    action: ACCEPT
    reason: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    supported_by:
    - reference_id: PMID:16980962
      supporting_text: Kinase activity of mutant LRRK2 mediates neuronal toxicity.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:17200152
  review:
    summary: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    action: ACCEPT
    reason: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    supported_by:
    - reference_id: PMID:17200152
      supporting_text: Jan 2. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:17442267
  review:
    summary: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    action: ACCEPT
    reason: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    supported_by:
    - reference_id: PMID:17442267
      supporting_text: The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16321986
  review:
    summary: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    action: ACCEPT
    reason: Protein kinase activity is a core function of LRRK2, phosphorylating Rab GTPases and other substrates.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16321986
  review:
    summary: Cytoplasm is a major localization for LRRK2.
    action: ACCEPT
    reason: Cytoplasm is a major localization for LRRK2.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:16352719
  review:
    summary: Cytoplasm is a major localization for LRRK2.
    action: ACCEPT
    reason: Cytoplasm is a major localization for LRRK2.
    supported_by:
    - reference_id: PMID:16352719
      supporting_text: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
- term:
    id: GO:0031398
    label: positive regulation of protein ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:16352719
  review:
    summary: Positive regulation of protein ubiquitination - related to parkin interaction.
    action: KEEP_AS_NON_CORE
    reason: Positive regulation of protein ubiquitination - related to parkin interaction.
    supported_by:
    - reference_id: PMID:16352719
      supporting_text: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:16321986
  review:
    summary: Protein homodimerization activity - LRRK2 dimerization is well-documented.
    action: ACCEPT
    reason: Protein homodimerization activity - LRRK2 dimerization is well-documented.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
- term:
    id: GO:0046777
    label: protein autophosphorylation
  evidence_type: IDA
  original_reference_id: PMID:16321986
  review:
    summary: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    action: ACCEPT
    reason: Protein autophosphorylation is well-documented for LRRK2, including Ser1292 as an activity marker.
    supported_by:
    - reference_id: PMID:16321986
      supporting_text: Dec 1. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
core_functions:
- molecular_function:
    id: GO:0004674
    label: protein serine/threonine kinase activity
  description: LRRK2 contains a kinase domain that phosphorylates Rab GTPases at threonine residues in their switch II regions. Primary substrates include Rab8A (Thr72), Rab10 (Thr73), Rab12 (Thr73), and Rab29 (Thr71).
- molecular_function:
    id: GO:0003924
    label: GTPase activity
  description: The ROC (Ras of complex proteins) domain of LRRK2 binds and hydrolyzes GTP. GTP binding and hydrolysis regulate kinase domain activity through intramolecular signaling.
- molecular_function:
    id: GO:0005525
    label: GTP binding
  description: LRRK2 ROC domain binds GTP, which is essential for regulating kinase activity. GTP binding status affects the conformation and enzymatic output of the protein.
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16269541
  title: Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity.
  findings: []
- id: PMID:16321986
  title: The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity.
  findings: []
- id: PMID:16352719
  title: Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration.
  findings: []
- id: PMID:16980962
  title: Kinase activity of mutant LRRK2 mediates neuronal toxicity.
  findings: []
- id: PMID:17114044
  title: The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
  findings: []
- id: PMID:17120249
  title: Localization of LRRK2 to membranous and vesicular structures in mammalian brain.
  findings: []
- id: PMID:17200152
  title: Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.
  findings: []
- id: PMID:17260967
  title: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.
  findings: []
- id: PMID:17400507
  title: Identification of potential protein interactors of Lrrk2.
  findings: []
- id: PMID:17442267
  title: The R1441C mutation of LRRK2 disrupts GTP hydrolysis.
  findings: []
- id: PMID:18230735
  title: Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase.
  findings: []
- id: PMID:18367605
  title: The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2.
  findings: []
- id: PMID:18397888
  title: The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation.
  findings: []
- id: PMID:18445495
  title: LRRK2 regulates synaptic vesicle endocytosis.
  findings: []
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:19176810
  title: The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.
  findings: []
- id: PMID:19196961
  title: CHIP regulates leucine-rich repeat kinase-2 ubiquitination, degradation, and toxicity.
  findings: []
- id: PMID:19302196
  title: The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro.
  findings: []
- id: PMID:19559761
  title: Interaction of elongation factor 1-alpha with leucine-rich repeat kinase 2 impairs kinase activity and microtubule bundling in vitro.
  findings: []
- id: PMID:19576176
  title: 'Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.'
  findings: []
- id: PMID:19625296
  title: Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways.
  findings: []
- id: PMID:19640926
  title: LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model.
  findings: []
- id: PMID:19692353
  title: Leucine-Rich Repeat Kinase 2 interacts with Parkin, DJ-1 and PINK-1 in a Drosophila melanogaster model of Parkinson's disease.
  findings: []
- id: PMID:19712061
  title: 'Homo- and heterodimerization of ROCO kinases: LRRK2 kinase inhibition by the LRRK2 ROCO fragment.'
  findings: []
- id: PMID:19733152
  title: The Parkinson's disease kinase LRRK2 autophosphorylates its GTPase domain at multiple sites.
  findings: []
- id: PMID:20067578
  title: MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2.
  findings: []
- id: PMID:20144646
  title: 'Heterodimerization of Lrrk1-Lrrk2: Implications for LRRK2-associated Parkinson disease.'
  findings: []
- id: PMID:20173330
  title: 'LRRK2 and the stress response: interaction with MKKs and JNK-interacting proteins.'
  findings: []
- id: PMID:20515039
  title: Membrane localization of LRRK2 is associated with increased formation of the highly active LRRK2 dimer and changes in its phosphorylation.
  findings: []
- id: PMID:20642453
  title: 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization.
  findings: []
- id: PMID:20659558
  title: Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.
  findings: []
- id: PMID:20671708
  title: Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression.
  findings: []
- id: PMID:21048939
  title: ARHGEF7 (Beta-PIX) acts as guanine nucleotide exchange factor for leucine-rich repeat kinase 2.
  findings: []
- id: PMID:21073465
  title: Insight into the mode of action of the LRRK2 Y1699C pathogenic mutant.
  findings: []
- id: PMID:21159966
  title: LRRK2 kinase regulates synaptic morphology through distinct substrates at the presynaptic and postsynaptic compartments of the Drosophila neuromuscular junction.
  findings: []
- id: PMID:21168496
  title: Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice.
  findings: []
- id: PMID:21307259
  title: LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool.
  findings: []
- id: PMID:21362567
  title: LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress.
  findings: []
- id: PMID:21370995
  title: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
  findings: []
- id: PMID:21454543
  title: Rac1 protein rescues neurite retraction caused by G2019S leucine-rich repeat kinase 2 (LRRK2).
  findings: []
- id: PMID:21563316
  title: Synaptic vesicle trafficking and Parkinson's disease.
  findings: []
- id: PMID:21658387
  title: 'LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: impairment of the kinase activity by Parkinson''s disease-associated mutations.'
  findings: []
- id: PMID:21696411
  title: 'LRRK2 expression in idiopathic and G2019S positive Parkinson''s disease subjects: a morphological and quantitative study.'
  findings: []
- id: PMID:21850687
  title: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
  findings: []
- id: PMID:21857923
  title: Dysregulated LRRK2 signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans.
  findings: []
- id: PMID:21983832
  title: The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease.
  findings: []
- id: PMID:22012985
  title: Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP.
  findings: []
- id: PMID:22228096
  title: LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1.
  findings: []
- id: PMID:22303461
  title: 'LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth.'
  findings: []
- id: PMID:22363216
  title: GTPase activity and neuronal toxicity of Parkinson's disease-associated LRRK2 is regulated by ArfGAP1.
  findings: []
- id: PMID:22423108
  title: 'ArfGAP1 is a GTPase activating protein for LRRK2: reciprocal regulation of ArfGAP1 by LRRK2.'
  findings: []
- id: PMID:22612223
  title: The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation.
  findings: []
- id: PMID:22639965
  title: Leucine-rich repeat kinase 2 disturbs mitochondrial dynamics via Dynamin-like protein.
  findings: []
- id: PMID:22664934
  title: Comparison of tear protein levels in breast cancer patients and healthy controls using a de novo proteomic approach.
  findings: []
- id: PMID:22736029
  title: G2019S leucine-rich repeat kinase 2 causes uncoupling protein-mediated mitochondrial depolarization.
  findings: []
- id: PMID:22764206
  title: Pharmacological rescue of mitochondrial deficits in iPSC-derived neural cells from patients with familial Parkinson's disease.
  findings: []
- id: PMID:22899650
  title: LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6.
  findings: []
- id: PMID:22952686
  title: Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers.
  findings: []
- id: PMID:22988876
  title: The importance of Wnt signalling for neurodegeneration in Parkinson's disease.
  findings: []
- id: PMID:22998870
  title: LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis.
  findings: []
- id: PMID:23075850
  title: Progressive degeneration of human neural stem cells caused by pathogenic LRRK2.
  findings: []
- id: PMID:23183827
  title: LRRK2 interactions with α-synuclein in Parkinson's disease brains and in cell models.
  findings: []
- id: PMID:23220480
  title: 'Dominant-negative effects of LRRK2 heterodimers: a possible mechanism of neurodegeneration in Parkinson''s disease caused by LRRK2 I2020T mutation.'
  findings: []
- id: PMID:23241358
  title: GTPase activity regulates kinase activity and cellular phenotypes of Parkinson's disease-associated LRRK2.
  findings: []
- id: PMID:23395371
  title: RAB7L1 interacts with LRRK2 to modify intraneuronal protein sorting and Parkinson's disease risk.
  findings: []
- id: PMID:23455607
  title: Interplay of LRRK2 with chaperone-mediated autophagy.
  findings: []
- id: PMID:23628791
  title: Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.
  findings: []
- id: PMID:23813973
  title: Inhibition of excessive mitochondrial fission reduced aberrant autophagy and neuronal damage caused by LRRK2 G2019S mutation.
  findings: []
- id: PMID:23916833
  title: Inhibition of LRRK2 kinase activity stimulates macroautophagy.
  findings: []
- id: PMID:23937259
  title: Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle.
  findings: []
- id: PMID:23949442
  title: LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25.
  findings: []
- id: PMID:24113872
  title: LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.
  findings: []
- id: PMID:24115276
  title: The regulation and deregulation of Wnt signaling by PARK genes in health and disease.
  findings: []
- id: PMID:24165324
  title: Leucine-rich repeat kinase 2 regulates tau phosphorylation through direct activation of glycogen synthase kinase-3β.
  findings: []
- id: PMID:24211199
  title: Pathogenic Parkinson's disease mutations across the functional domains of LRRK2 alter the autophagic/lysosomal response to starvation.
  findings: []
- id: PMID:24252804
  title: The role of oxidative stress in Parkinson's disease.
  findings: []
- id: PMID:24275654
  title: A direct interaction between leucine-rich repeat kinase 2 and specific β-tubulin isoforms regulates tubulin acetylation.
  findings: []
- id: PMID:24282027
  title: Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily.
  findings: []
- id: PMID:24351927
  title: Parkinson-related LRRK2 mutation R1441C/G/H impairs PKA phosphorylation of LRRK2 and disrupts its interaction with 14-3-3.
  findings: []
- id: PMID:24403142
  title: Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies.
  findings: []
- id: PMID:24459295
  title: Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila.
  findings: []
- id: PMID:24464040
  title: LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
  findings: []
- id: PMID:24510904
  title: Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease.
  findings: []
- id: PMID:24576675
  title: LRRK2, but not pathogenic mutants, protects against H2O2 stress depending on mitochondrial function and endocytosis in a yeast model.
  findings: []
- id: PMID:24591621
  title: Parkinson disease-associated mutation R1441H in LRRK2 prolongs the "active state" of its GTPase domain.
  findings: []
- id: PMID:24687852
  title: Leucine-rich repeat kinase 2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain.
  findings: []
- id: PMID:24695735
  title: The Parkinson disease-linked LRRK2 protein mutation I2020T stabilizes an active state conformation leading to increased kinase activity.
  findings: []
- id: PMID:24725412
  title: Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.
  findings: []
- id: PMID:24754922
  title: MAP1B rescues LRRK2 mutant-mediated cytotoxicity.
  findings: []
- id: PMID:24794857
  title: A Parkinson's disease gene regulatory network identifies the signaling protein RGS2 as a modulator of LRRK2 activity and neuronal toxicity.
  findings: []
- id: PMID:24904275
  title: LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex.
  findings: []
- id: PMID:24947832
  title: Differential protein-protein interactions of LRRK1 and LRRK2 indicate roles in distinct cellular signaling pathways.
  findings: []
- id: PMID:25009464
  title: LRRK2 kinase activity and biology are not uniformly predicted by its autophosphorylation and cellular phosphorylation site status.
  findings: []
- id: PMID:25201882
  title: Leucine-rich repeat kinase 2 regulates Sec16A at ER exit sites to allow ER-Golgi export.
  findings: []
- id: PMID:25360523
  title: LRRK2 transport is regulated by its novel interacting partner Rab32.
  findings: []
- id: PMID:25416817
  title: Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition.
  findings: []
- id: PMID:25446991
  title: Threonine 56 phosphorylation of Bcl-2 is required for LRRK2 G2019S-induced mitochondrial depolarization and autophagy.
  findings: []
- id: PMID:25500533
  title: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.
  findings: []
- id: PMID:25501810
  title: LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism.
  findings: []
- id: PMID:25605758
  title: An early endosome regulator, Rab5b, is an LRRK2 kinase substrate.
  findings: []
- id: PMID:26014385
  title: LRRK2 Promotes Tau Accumulation, Aggregation and Release.
  findings: []
- id: PMID:26751287
  title: The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer.
  findings: []
- id: PMID:26824392
  title: Phosphoproteomics reveals that Parkinson's disease kinase LRRK2 regulates a subset of Rab GTPases.
  findings: []
- id: PMID:26894577
  title: Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2.
  findings: []
- id: PMID:27013965
  title: Protective LRRK2 R1398H Variant Enhances GTPase and Wnt Signaling Activity.
  findings: []
- id: PMID:27273569
  title: Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1.
  findings: []
- id: PMID:27314038
  title: G2385R and I2020T Mutations Increase LRRK2 GTPase Activity.
  findings: []
- id: PMID:27357661
  title: Structural model of the dimeric Parkinson's protein LRRK2 reveals a compact architecture involving distant interdomain contacts.
  findings: []
- id: PMID:27424887
  title: LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts.
  findings: []
- id: PMID:27830463
  title: LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation.
  findings: []
- id: PMID:28202711
  title: Structural interface between LRRK2 and 14-3-3 protein.
  findings: []
- id: PMID:28720718
  title: Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease.
  findings: []
- id: PMID:29513927
  title: Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins.
  findings: []
- id: PMID:29519959
  title: P62/SQSTM1 is a novel leucine-rich repeat kinase 2 (LRRK2) substrate that enhances neuronal toxicity.
  findings: []
- id: PMID:29541021
  title: The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1.
  findings: []
- id: PMID:30398148
  title: A pathway for Parkinson's Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain.
  findings: []
- id: PMID:31046837
  title: Parkinson's disease-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes.
  findings: []
- id: PMID:31552791
  title: LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain.
  findings: []
- id: PMID:32017888
  title: Structural Basis for Rab8a Recruitment of RILPL2 via LRRK2 Phosphorylation of Switch 2.
  findings: []
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
- id: PMID:33938021
  title: Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.
  findings: []
- id: PMID:38127736
  title: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
  findings: []
- id: PMID:38858457
  title: Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.
  findings: []
- id: Reactome:R-HSA-8857565
  title: Phosphorylated GPNMB recruits PTK6 and LRRK2 in the presence of LINC01139
  findings: []
- id: Reactome:R-HSA-8857577
  title: LINC01139 facilitates PTK6 autophosphorylation
  findings: []
- id: Reactome:R-HSA-8857583
  title: LINC01139 promotes phosphorylation of HIF1A by PTK6
  findings: []
- id: Reactome:R-HSA-9634702
  title: LINC01139 promotes phosphorylation of HIF1A by LRRK2
  findings: []
- id: file:human/LRRK2/LRRK2-deep-research-falcon.md
  title: Deep research report on LRRK2
  findings: []

LRRK2

Gene Description

Existing Annotations Review

Core Functions

LRRK2 contains a kinase domain that phosphorylates Rab GTPases at threonine residues in their switch II regions. Primary substrates include Rab8A (Thr72), Rab10 (Thr73), Rab12 (Thr73), and Rab29 (Thr71).

The ROC (Ras of complex proteins) domain of LRRK2 binds and hydrolyzes GTP. GTP binding and hydrolysis regulate kinase domain activity through intramolecular signaling.

LRRK2 ROC domain binds GTP, which is essential for regulating kinase activity. GTP binding status affects the conformation and enzymatic output of the protein.

References

📚 Additional Documentation

Deep Research Bioreason

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Bioreason Rl

BioReason Chat Export

Thinking Trace

Functional Summary

UniProt Summary

InterPro Domains

GO Terms

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Citations

Bioreason Rl Review

BioReason-Pro RL Review: LRRK2 (human)

Functional Summary Review

Notes on thinking trace

📄 View Raw YAML