SORL1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005794 Golgi apparatus	IBA GO_REF:0000033	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0006892 post-Golgi vesicle-mediated transport	IBA GO_REF:0000033	ACCEPT	Summary: SorLA participates in vesicular transport from the TGN onward, dispatching itself and cargo to endosomes and the cell surface. Reason: Core trafficking step in SorLA's sorting itinerary (IBA/IDA).
GO:0016020 membrane	IBA GO_REF:0000033	ACCEPT	Summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system. Reason: Correct but generic; consistent with the transmembrane receptor.
GO:0006622 protein targeting to lysosome	IBA GO_REF:0000033	ACCEPT	Summary: SorLA routes select cargo (LPL, GDNF, IL6, APOA5, amyloid-beta) to lysosomes for degradation, a defined branch of its sorting output. Reason: Core degradative sorting branch of the receptor (IBA/IDA).
GO:0045053 protein retention in Golgi apparatus	IBA GO_REF:0000033	ACCEPT	Summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing. Reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
GO:0000139 Golgi membrane	IEA GO_REF:0000044	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0005041 low-density lipoprotein particle receptor activity	IEA GO_REF:0000117	ACCEPT	Summary: SorLA functions as an LDL-receptor-family member with complement-type ligand-binding repeats that bind lipoprotein and LRPAP1/RAP ligands. Reason: Core receptor activity defining SorLA's LDLR-family identity.
GO:0005576 extracellular region	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0005764 lysosome	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: SorLA routes select cargo (LPL, GDNF, APOA5, amyloid-beta) toward lysosomes for catabolism; the lysosome is a destination of its degradative sorting branch. Reason: Terminal destination compartment downstream of SorLA's sorting decisions.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting. Reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
GO:0005794 Golgi apparatus	IEA GO_REF:0000044	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0005829 cytosol	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: SorLA is a single-pass type I membrane protein; only a small RIP-released C-terminal fragment is cytosolic, so a bulk cytosol annotation overstates its distribution. Reason: IEA cytosol overstates localization of an integral membrane protein.
GO:0005886 plasma membrane	IEA GO_REF:0000044	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0010008 endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting. Reason: Membrane localization underpins SorLA's endosomal sorting function.
GO:0016020 membrane	IEA GO_REF:0000120	ACCEPT	Summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system. Reason: Correct but generic; consistent with the transmembrane receptor.
GO:0030658 transport vesicle membrane	IEA GO_REF:0000044	ACCEPT	Summary: SorLA is carried in transport/secretory and endosome-to-TGN retrograde vesicles that shuttle it and its cargo between compartments. Reason: Vesicle-membrane localization matches its trafficking itinerary (UniProt: retrograde vesicles).
GO:0031901 early endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval. Reason: Membrane sub-localization supporting endosomal cargo sorting.
GO:0032585 multivesicular body membrane	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: MVB-membrane localization is consistent with SorLA delivering cargo to the lysosomal degradation pathway. Reason: Late-endosomal membrane, secondary to the core TGN/endosome retrieval role.
GO:0055038 recycling endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors. Reason: Membrane sub-localization for SorLA's recycling function.
GO:0005515 protein binding	IPI PMID:11821067 The sorLA cytoplasmic domain interacts with GGA1 and -2 and ...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:17326667 Apolipoprotein A-V interaction with members of the low densi...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:23333276 SorLA controls neurotrophic activity by sorting of GDNF and ...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:25643321 Structural basis for amyloidogenic peptide recognition by so...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:26053850 The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA) Prote...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:26858303 Cytokine-Like Factor 1, an Essential Facilitator of Cardiotr...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:28265003 SorLA in Interleukin-6 Signaling and Turnover.	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:30679749 HSPA12A targets the cytoplasmic domain and affects the traff...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0002024 diet induced thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA's metabolic regulation of adipose energy expenditure extends to diet-induced thermogenesis, a systemic consequence of its ectodomain activity. Reason: Pleiotropic energy-balance phenotype, downstream of metabolic signaling roles.
GO:0005641 nuclear envelope lumen	IEA GO_REF:0000107	UNDECIDED	Summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed. Reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
GO:0005771 multivesicular body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA is seen in MVBs/late endosomes as part of cargo routing toward lysosomal degradation (e.g. LPL, GDNF). Reason: Downstream late-endosomal station of the degradative arm of SorLA sorting.
GO:0006605 protein targeting	IEA GO_REF:0000107	ACCEPT	Summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role. Reason: Core process: directing proteins to their correct intracellular location.
GO:0010897 negative regulation of triglyceride catabolic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: By trafficking LPL to lysosomes and degrading it, SorLA reduces lipase activity and triglyceride catabolism; a metabolic consequence of degradative sorting. Reason: Lipid-metabolism effect downstream of SorLA-mediated LPL turnover.
GO:0016477 cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA modulates migration of smooth-muscle and myeloid cells through uPAR/PLAUR surface regulation, a pleiotropic consequence of its receptor trafficking. Reason: Generic pleiotropic migration role secondary to ligand trafficking.
GO:0019828 aspartic-type endopeptidase inhibitor activity	IEA GO_REF:0000107	MODIFY	Summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition. Reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation. Proposed replacements: negative regulation of amyloid-beta formation
GO:0030514 negative regulation of BMP signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The SorLA N-terminal ectodomain inhibits BMP/Smad signaling in adipose tissue to restrain energy expenditure; a metabolic, ectodomain-mediated role. Reason: Pleiotropic metabolic signaling effect of the soluble ectodomain (IEA/ISS).
GO:0038020 insulin receptor recycling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA recycles internalized INSR via the Golgi to the surface, raising INSR surface levels in adipocytes; a tissue-specific instance of its recycling-sorting role. Reason: Cargo-specific recycling event downstream of SorLA's general recycling activity.
GO:0043025 neuronal cell body	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA is enriched in neuronal soma, consistent with its high brain expression and role in neuronal cargo (APP, TrkB, GDNF) trafficking. Reason: Cell-type-specific localization reflecting neuronal expression, not a distinct core compartment.
GO:0045053 protein retention in Golgi apparatus	IEA GO_REF:0000107	ACCEPT	Summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing. Reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
GO:0046628 positive regulation of insulin receptor signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: By increasing INSR surface expression through recycling, SorLA strengthens insulin signaling in adipose tissue, a pleiotropic downstream consequence. Reason: Signaling effect secondary to SorLA-mediated INSR recycling.
GO:0050768 negative regulation of neurogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA influences neuronal development consistent with its high brain expression and trafficking of neurotrophic cargo (BDNF/TrkB, GDNF). Reason: Developmental role downstream of neurotrophic-receptor sorting (IEA/ISS).
GO:0097356 perinucleolar compartment	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: No evidence places this transmembrane sorting receptor in the perinucleolar compartment; the IEA call is implausible for SorLA. Reason: Implausible nuclear sub-compartment for a membrane sorting receptor; electronic over-annotation.
GO:0099638 endosome to plasma membrane protein transport	IEA GO_REF:0000107	ACCEPT	Summary: SorLA promotes return of internalized receptors (INSR, HER2) from endosomes to the plasma membrane, a recycling arm of its sorting activity. Reason: Core recycling route mediated by SorLA (UniProt: HER2/INSR recycling).
GO:1900168 positive regulation of glial cell-derived neurotrophic factor production	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: SorLA controls regulated (vs constitutive) GDNF secretion by sorting GDNF and its receptors, influencing GDNF availability; a neurotrophic-specific role. Reason: Cargo-specific neurotrophic effect downstream of GDNF sorting.
GO:1902430 negative regulation of amyloid-beta formation	IEA GO_REF:0000107	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:1902992 negative regulation of amyloid precursor protein catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting. Reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
GO:1902997 negative regulation of neurofibrillary tangle assembly	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: SorLA's primary action is on APP/Abeta trafficking; an effect on tau neurofibrillary-tangle assembly is at best indirect and rests only on electronic/ISS inference. Reason: Tau-tangle effect is speculative and indirect; electronic over-annotation.
GO:1904179 positive regulation of adipose tissue development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Through its metabolic actions (INSR recycling, BMP inhibition, LPL turnover) SorLA influences adipose tissue development; a pleiotropic systemic role. Reason: Systemic metabolic/developmental role secondary to its trafficking functions.
GO:1990845 adaptive thermogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Soluble SorLA represses adipose thermogenesis via BMP/Smad inhibition, shifting energy balance toward storage; a metabolic role of the ectodomain. Reason: Pleiotropic metabolic phenotype of the shed ectodomain (IEA/ISS).
GO:0038024 cargo receptor activity	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface. Reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
GO:0038024 cargo receptor activity	IDA PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface. Reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
GO:0038024 cargo receptor activity	TAS PMID:9157966 A novel mosaic protein containing LDL receptor elements is h...	ACCEPT	Summary: This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface. Reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
GO:0000139 Golgi membrane	EXP PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0000139 Golgi membrane	EXP PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0000139 Golgi membrane	EXP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0000139 Golgi membrane	EXP PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0000139 Golgi membrane	EXP PMID:21994944 Sorting protein-related receptor SorLA controls regulated se...	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0005576 extracellular region	EXP PMID:11082041 Ectodomain shedding, translocation and synthesis of SorLA ar...	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0005576 extracellular region	EXP PMID:15053742 The mosaic receptor sorLA/LR11 binds components of the plasm...	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0005576 extracellular region	EXP PMID:16393139 Tumour necrosis factor alpha-converting enzyme mediates ecto...	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0005576 extracellular region	EXP PMID:16531402 SorLA signaling by regulated intramembrane proteolysis.	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	KEEP AS NON CORE	Summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting. Reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
GO:0005789 endoplasmic reticulum membrane	EXP PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	KEEP AS NON CORE	Summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting. Reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
GO:0005886 plasma membrane	EXP PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0005886 plasma membrane	EXP PMID:14764453 LR11, an LDL receptor gene family member, is a novel regulat...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0005886 plasma membrane	EXP PMID:15053742 The mosaic receptor sorLA/LR11 binds components of the plasm...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0005886 plasma membrane	EXP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0005886 plasma membrane	EXP PMID:31138794 SORLA regulates endosomal trafficking and oncogenic fitness ...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0010008 endosome membrane	EXP PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting. Reason: Membrane localization underpins SorLA's endosomal sorting function.
GO:0010008 endosome membrane	EXP PMID:23333276 SorLA controls neurotrophic activity by sorting of GDNF and ...	ACCEPT	Summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting. Reason: Membrane localization underpins SorLA's endosomal sorting function.
GO:0031901 early endosome membrane	EXP PMID:17646382 Sorting by the cytoplasmic domain of the amyloid precursor p...	ACCEPT	Summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval. Reason: Membrane sub-localization supporting endosomal cargo sorting.
GO:0031901 early endosome membrane	EXP PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval. Reason: Membrane sub-localization supporting endosomal cargo sorting.
GO:0031901 early endosome membrane	EXP PMID:31138794 SORLA regulates endosomal trafficking and oncogenic fitness ...	ACCEPT	Summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval. Reason: Membrane sub-localization supporting endosomal cargo sorting.
GO:0055038 recycling endosome membrane	EXP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors. Reason: Membrane sub-localization for SorLA's recycling function.
GO:0055038 recycling endosome membrane	EXP PMID:31138794 SORLA regulates endosomal trafficking and oncogenic fitness ...	ACCEPT	Summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors. Reason: Membrane sub-localization for SorLA's recycling function.
GO:0001960 negative regulation of cytokine-mediated signaling pathway	IDA PMID:26858303 Cytokine-Like Factor 1, an Essential Facilitator of Cardiotr...	KEEP AS NON CORE	Summary: SorLA dampens cytokine signaling by internalizing and degrading IL6/CLCF1-CRLF1-CNTFR complexes, a downstream effect of its endocytic-degradative sorting. Reason: Signaling modulation secondary to SorLA cargo internalization and turnover.
GO:0005886 plasma membrane	IDA PMID:26858303 Cytokine-Like Factor 1, an Essential Facilitator of Cardiotr...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0038024 cargo receptor activity	IDA PMID:26858303 Cytokine-Like Factor 1, an Essential Facilitator of Cardiotr...	ACCEPT	Summary: This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface. Reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
GO:1905146 lysosomal protein catabolic process	IDA PMID:26858303 Cytokine-Like Factor 1, an Essential Facilitator of Cardiotr...	KEEP AS NON CORE	Summary: Lysosomal degradation of SorLA-delivered cargo is a downstream consequence of its degradative sorting branch rather than the proximal sorting activity itself. Reason: Downstream catabolic outcome of SorLA's lysosomal targeting.
GO:0031901 early endosome membrane	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval. Reason: Membrane sub-localization supporting endosomal cargo sorting.
GO:0042147 retrograde transport, endosome to Golgi	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA's cytosolic tail engages retromer (VPS29) and GGA adaptors to retrieve itself and cargo from endosomes back to the TGN. Reason: Central retrieval route defining SorLA's sorting behaviour (IDA).
GO:0140318 protein transporter activity	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA physically carries bound cargo proteins between compartments, consistent with its cargo-receptor role in directing protein localization. Reason: Captures the cargo-carrying activity central to SorLA's sorting function (IDA).
GO:1902430 negative regulation of amyloid-beta formation	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:0019828 aspartic-type endopeptidase inhibitor activity	IDA PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	MODIFY	Summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition. Reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation. Proposed replacements: negative regulation of amyloid-beta formation
GO:0019828 aspartic-type endopeptidase inhibitor activity	IMP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	MODIFY	Summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition. Reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation. Proposed replacements: negative regulation of amyloid-beta formation
GO:0019828 aspartic-type endopeptidase inhibitor activity	IMP PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	MODIFY	Summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition. Reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation. Proposed replacements: negative regulation of amyloid-beta formation
GO:1902992 negative regulation of amyloid precursor protein catabolic process	IDA PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	ACCEPT	Summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting. Reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
GO:1902992 negative regulation of amyloid precursor protein catabolic process	IMP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting. Reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
GO:1902992 negative regulation of amyloid precursor protein catabolic process	IMP PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	ACCEPT	Summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting. Reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
GO:0005515 protein binding	IPI PMID:11294867 Activation and functional characterization of the mosaic rec...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005794 Golgi apparatus	IDA PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0006898 receptor-mediated endocytosis	IDA PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: SorLA mediates AP-2/clathrin-dependent internalization of surface ligands (uPA-PAI1, APOA5, IL6, HER2), feeding them into its endosomal sorting itinerary. Reason: Core uptake step of SorLA's cargo-sorting cycle (IDA/TAS).
GO:0007218 neuropeptide signaling pathway	IDA PMID:11294867 Activation and functional characterization of the mosaic rec...	KEEP AS NON CORE	Summary: SorLA's interaction with neuropeptides (HA) links it to neuropeptide signaling, a downstream context of its ligand-binding capacity. Reason: Signaling context downstream of SorLA neuropeptide binding.
GO:0009986 cell surface	IDA PMID:11294867 Activation and functional characterization of the mosaic rec...	ACCEPT	Summary: Surface-exposed SorLA binds ligands (e.g. APP, IL6, uPAR) and mediates their internalization; the surface pool also undergoes ectodomain shedding. Reason: Cell-surface presence is required for SorLA receptor-mediated endocytosis (IDA).
GO:0042923 neuropeptide binding	IPI PMID:11082041 Ectodomain shedding, translocation and synthesis of SorLA ar...	KEEP AS NON CORE	Summary: The VPS10P domain binds neuropeptides such as head activator (HA) and neurotensin; a specific partner-binding activity peripheral to the core sorting role. Reason: Partner-specific ligand binding; ancillary to the defining cargo-receptor activity.
GO:0042923 neuropeptide binding	IPI PMID:11294867 Activation and functional characterization of the mosaic rec...	KEEP AS NON CORE	Summary: The VPS10P domain binds neuropeptides such as head activator (HA) and neurotensin; a specific partner-binding activity peripheral to the core sorting role. Reason: Partner-specific ligand binding; ancillary to the defining cargo-receptor activity.
GO:0031333 negative regulation of protein-containing complex assembly	IMP PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	KEEP AS NON CORE	Summary: By sequestering APP and modulating BACE1 access, SorLA can limit assembly of processing complexes; an indirect effect of its cargo-binding behaviour. Reason: Indirect complex-assembly effect downstream of SorLA ligand sequestration (IMP).
GO:0005515 protein binding	IPI PMID:21994944 Sorting protein-related receptor SorLA controls regulated se...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005794 Golgi apparatus	IDA PMID:21994944 Sorting protein-related receptor SorLA controls regulated se...	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0005886 plasma membrane	IDA PMID:21994944 Sorting protein-related receptor SorLA controls regulated se...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:1900168 positive regulation of glial cell-derived neurotrophic factor production	IDA PMID:21994944 Sorting protein-related receptor SorLA controls regulated se...	KEEP AS NON CORE	Summary: SorLA controls regulated (vs constitutive) GDNF secretion by sorting GDNF and its receptors, influencing GDNF availability; a neurotrophic-specific role. Reason: Cargo-specific neurotrophic effect downstream of GDNF sorting.
GO:0005515 protein binding	IPI PMID:30448281 Soluble LR11 competes with amyloid β in binding to cerebrosp...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0006605 protein targeting	IDA PMID:27322061 SORLA facilitates insulin receptor signaling in adipocytes a...	ACCEPT	Summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role. Reason: Core process: directing proteins to their correct intracellular location.
GO:0010897 negative regulation of triglyceride catabolic process	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: By trafficking LPL to lysosomes and degrading it, SorLA reduces lipase activity and triglyceride catabolism; a metabolic consequence of degradative sorting. Reason: Lipid-metabolism effect downstream of SorLA-mediated LPL turnover.
GO:0038020 insulin receptor recycling	IDA PMID:27322061 SORLA facilitates insulin receptor signaling in adipocytes a...	KEEP AS NON CORE	Summary: SorLA recycles internalized INSR via the Golgi to the surface, raising INSR surface levels in adipocytes; a tissue-specific instance of its recycling-sorting role. Reason: Cargo-specific recycling event downstream of SorLA's general recycling activity.
GO:0046628 positive regulation of insulin receptor signaling pathway	IDA PMID:27322061 SORLA facilitates insulin receptor signaling in adipocytes a...	KEEP AS NON CORE	Summary: By increasing INSR surface expression through recycling, SorLA strengthens insulin signaling in adipose tissue, a pleiotropic downstream consequence. Reason: Signaling effect secondary to SorLA-mediated INSR recycling.
GO:1904179 positive regulation of adipose tissue development	IDA PMID:27322061 SORLA facilitates insulin receptor signaling in adipocytes a...	KEEP AS NON CORE	Summary: Through its metabolic actions (INSR recycling, BMP inhibition, LPL turnover) SorLA influences adipose tissue development; a pleiotropic systemic role. Reason: Systemic metabolic/developmental role secondary to its trafficking functions.
GO:0002024 diet induced thermogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SorLA's metabolic regulation of adipose energy expenditure extends to diet-induced thermogenesis, a systemic consequence of its ectodomain activity. Reason: Pleiotropic energy-balance phenotype, downstream of metabolic signaling roles.
GO:0005515 protein binding	IPI PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005768 endosome	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: SorLA cycles through endosomes, capturing internalized cargo (APP, LPL, INSR, HER2) for retrieval to the TGN or routing to lysosomes. Reason: Endosome is a defining compartment of SorLA's retrieval/sorting itinerary.
GO:0005769 early endosome	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing. Reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
GO:0005771 multivesicular body	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	KEEP AS NON CORE	Summary: SorLA is seen in MVBs/late endosomes as part of cargo routing toward lysosomal degradation (e.g. LPL, GDNF). Reason: Downstream late-endosomal station of the degradative arm of SorLA sorting.
GO:0005783 endoplasmic reticulum	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	KEEP AS NON CORE	Summary: SorLA transits the ER during biosynthesis and maturation, but its sorting activity acts downstream in the TGN/endosomal system rather than in the ER. Reason: Biosynthetic transit compartment, upstream of and peripheral to the core sorting cycle.
GO:0005794 Golgi apparatus	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0005886 plasma membrane	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0006605 protein targeting	IDA PMID:21385844 SorLA regulates the activity of lipoprotein lipase by intrac...	ACCEPT	Summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role. Reason: Core process: directing proteins to their correct intracellular location.
GO:0030514 negative regulation of BMP signaling pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: The SorLA N-terminal ectodomain inhibits BMP/Smad signaling in adipose tissue to restrain energy expenditure; a metabolic, ectodomain-mediated role. Reason: Pleiotropic metabolic signaling effect of the soluble ectodomain (IEA/ISS).
GO:1990845 adaptive thermogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Soluble SorLA represses adipose thermogenesis via BMP/Smad inhibition, shifting energy balance toward storage; a metabolic role of the ectodomain. Reason: Pleiotropic metabolic phenotype of the shed ectodomain (IEA/ISS).
GO:0005041 low-density lipoprotein particle receptor activity	TAS PMID:20005821 Overexpression of low-density lipoprotein receptor in the br...	ACCEPT	Summary: SorLA functions as an LDL-receptor-family member with complement-type ligand-binding repeats that bind lipoprotein and LRPAP1/RAP ligands. Reason: Core receptor activity defining SorLA's LDLR-family identity.
GO:0000139 Golgi membrane	TAS Reactome:R-HSA-8871506	ACCEPT	Summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP. Reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-8871494	ACCEPT	Summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting. Reason: Membrane localization underpins SorLA's endosomal sorting function.
GO:0010008 endosome membrane	TAS Reactome:R-HSA-8871506	ACCEPT	Summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting. Reason: Membrane localization underpins SorLA's endosomal sorting function.
GO:0050768 negative regulation of neurogenesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: SorLA influences neuronal development consistent with its high brain expression and trafficking of neurotrophic cargo (BDNF/TrkB, GDNF). Reason: Developmental role downstream of neurotrophic-receptor sorting (IEA/ISS).
GO:1902997 negative regulation of neurofibrillary tangle assembly	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: SorLA's primary action is on APP/Abeta trafficking; an effect on tau neurofibrillary-tangle assembly is at best indirect and rests only on electronic/ISS inference. Reason: Tau-tangle effect is speculative and indirect; electronic over-annotation.
GO:1902953 positive regulation of ER to Golgi vesicle-mediated transport	IMP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: SorLA promotes anterograde ER-to-Golgi transport of cargo, complementing its retrieval activity in establishing correct cargo localization. Reason: Trafficking-regulatory role consistent with its sorting function (IMP).
GO:1902966 positive regulation of protein localization to early endosome	IMP PMID:22621900 GGA1-mediated endocytic traffic of LR11/SorLA alters APP int...	ACCEPT	Summary: SorLA drives delivery of cargo into early endosomes en route to retrieval or degradation, an integral step of its sorting cycle. Reason: Direct manifestation of SorLA endosomal cargo sorting (IMP).
GO:0001540 amyloid-beta binding	IDA PMID:24523320 Lysosomal sorting of amyloid-β by the SORLA receptor is impa...	ACCEPT	Summary: SorLA directly binds amyloid-beta (and APP C99/Abeta40) via its ectodomain, enabling capture of newly produced Abeta for lysosomal clearance. Reason: Defining ligand interaction underlying SorLA's anti-amyloidogenic sorting (IDA/IPI).
GO:0005515 protein binding	IPI PMID:24001769 SORLA-dependent and -independent functions for PACS1 in cont...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005769 early endosome	IMP PMID:22621900 GGA1-mediated endocytic traffic of LR11/SorLA alters APP int...	ACCEPT	Summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing. Reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
GO:0005769 early endosome	IDA PMID:24001769 SORLA-dependent and -independent functions for PACS1 in cont...	ACCEPT	Summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing. Reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
GO:0005802 trans-Golgi network	IDA PMID:24001769 SORLA-dependent and -independent functions for PACS1 in cont...	ACCEPT	Summary: SorLA is predominantly localized to the TGN, the compartment where it retains APP and from which it dispatches cargo to endosomes. Reason: TGN is the principal steady-state site of this sorting receptor (UniProt: 'predominantly in the TGN').
GO:0006622 protein targeting to lysosome	IDA PMID:24523320 Lysosomal sorting of amyloid-β by the SORLA receptor is impa...	ACCEPT	Summary: SorLA routes select cargo (LPL, GDNF, IL6, APOA5, amyloid-beta) to lysosomes for degradation, a defined branch of its sorting output. Reason: Core degradative sorting branch of the receptor (IBA/IDA).
GO:0045732 positive regulation of protein catabolic process	IDA PMID:24523320 Lysosomal sorting of amyloid-β by the SORLA receptor is impa...	ACCEPT	Summary: By routing clients (LPL, GDNF, IL6, amyloid-beta) to lysosomes, SorLA promotes their catabolism as a downstream output of degradative sorting. Reason: Direct outcome of SorLA's lysosomal targeting branch (IDA).
GO:0055037 recycling endosome	IMP PMID:22621900 GGA1-mediated endocytic traffic of LR11/SorLA alters APP int...	ACCEPT	Summary: SorLA traffics through recycling endosomes, enabling cargo such as INSR and HER2 to be returned to the cell surface. Reason: Recycling-endosome residence supports SorLA-mediated receptor recycling (IMP).
GO:1902430 negative regulation of amyloid-beta formation	IDA PMID:22621900 GGA1-mediated endocytic traffic of LR11/SorLA alters APP int...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:1902430 negative regulation of amyloid-beta formation	IMP PMID:24001769 SORLA-dependent and -independent functions for PACS1 in cont...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:1902430 negative regulation of amyloid-beta formation	IMP PMID:24523320 Lysosomal sorting of amyloid-β by the SORLA receptor is impa...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:2001137 positive regulation of endocytic recycling	IMP PMID:22621900 GGA1-mediated endocytic traffic of LR11/SorLA alters APP int...	ACCEPT	Summary: SorLA enhances recycling of internalized cargo back to the surface, exemplified by HER2 recycling that sustains PI3K-dependent signaling. Reason: Core recycling-promoting activity of the sorting receptor (IMP).
GO:0001540 amyloid-beta binding	IPI PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	ACCEPT	Summary: SorLA directly binds amyloid-beta (and APP C99/Abeta40) via its ectodomain, enabling capture of newly produced Abeta for lysosomal clearance. Reason: Defining ligand interaction underlying SorLA's anti-amyloidogenic sorting (IDA/IPI).
GO:0005515 protein binding	IPI PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005641 nuclear envelope lumen	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	UNDECIDED	Summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed. Reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
GO:0005641 nuclear envelope lumen	IDA PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	UNDECIDED	Summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed. Reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
GO:0005783 endoplasmic reticulum	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	KEEP AS NON CORE	Summary: SorLA transits the ER during biosynthesis and maturation, but its sorting activity acts downstream in the TGN/endosomal system rather than in the ER. Reason: Biosynthetic transit compartment, upstream of and peripheral to the core sorting cycle.
GO:0006605 protein targeting	IDA PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	ACCEPT	Summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role. Reason: Core process: directing proteins to their correct intracellular location.
GO:0006892 post-Golgi vesicle-mediated transport	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: SorLA participates in vesicular transport from the TGN onward, dispatching itself and cargo to endosomes and the cell surface. Reason: Core trafficking step in SorLA's sorting itinerary (IBA/IDA).
GO:0031267 small GTPase binding	IPI PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	KEEP AS NON CORE	Summary: Reported binding to a small GTPase (e.g. RHOH) is a specific partner interaction not central to SorLA's cargo-sorting mechanism. Reason: Specific partner binding, peripheral to the core sorting function (IPI).
GO:0031985 Golgi cisterna	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: IDA localization to Golgi cisternae is consistent with SorLA's residence in the Golgi stack during cargo sorting and retrieval. Reason: Cisternal localization refines the core Golgi pool of this sorting receptor.
GO:0034067 protein localization to Golgi apparatus	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: By capturing and retrieving cargo to the Golgi/TGN, SorLA establishes the Golgi localization of clients such as APP. Reason: Direct consequence of SorLA's retrieval/retention activity (IDA).
GO:0045053 protein retention in Golgi apparatus	IDA PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing. Reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
GO:1902430 negative regulation of amyloid-beta formation	IDA PMID:16407538 Interaction of the cytosolic domains of sorLA/LR11 with the ...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:1902430 negative regulation of amyloid-beta formation	IMP PMID:17855360 SorLA/LR11 regulates processing of amyloid precursor protein...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:1902430 negative regulation of amyloid-beta formation	IMP PMID:21989385 Quantitative modelling of amyloidogenic processing and its i...	ACCEPT	Summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role. Reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	KEEP AS NON CORE	Summary: HDA detection of SorLA in exosomes is consistent with proteomic surveys; it is incidental to the receptor's intracellular sorting function. Reason: High-throughput proteomic localization; not a core functional site.
GO:0005515 protein binding	IPI PMID:14764453 LR11, an LDL receptor gene family member, is a novel regulat...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor. Reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
GO:0005576 extracellular region	IDA PMID:14764453 LR11, an LDL receptor gene family member, is a novel regulat...	KEEP AS NON CORE	Summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment. Reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
GO:0014910 regulation of smooth muscle cell migration	IDA PMID:14764453 LR11, an LDL receptor gene family member, is a novel regulat...	KEEP AS NON CORE	Summary: The shed SorLA ectodomain promotes smooth-muscle migration via increased uPAR surface display, a pleiotropic vascular role of the soluble fragment. Reason: Vascular phenotype downstream of ectodomain/uPAR handling, not core sorting.
GO:0016020 membrane	IDA PMID:14764453 LR11, an LDL receptor gene family member, is a novel regulat...	ACCEPT	Summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system. Reason: Correct but generic; consistent with the transmembrane receptor.
GO:0005768 endosome	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA cycles through endosomes, capturing internalized cargo (APP, LPL, INSR, HER2) for retrieval to the TGN or routing to lysosomes. Reason: Endosome is a defining compartment of SorLA's retrieval/sorting itinerary.
GO:0005794 Golgi apparatus	IDA PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated. Reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
GO:0006605 protein targeting	IMP PMID:16174740 Neuronal sorting protein-related receptor sorLA/LR11 regulat...	ACCEPT	Summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role. Reason: Core process: directing proteins to their correct intracellular location.
GO:0030169 low-density lipoprotein particle binding	IPI PMID:17326667 Apolipoprotein A-V interaction with members of the low densi...	ACCEPT	Summary: Through its LDLR-class complement repeats SorLA binds LDL particles, reflecting its membership in the LDL-receptor gene family. Reason: Direct ligand-binding activity characteristic of this LDLR-family receptor (IPI).
GO:0005886 plasma membrane	TAS PMID:9157966 A novel mosaic protein containing LDL receptor elements is h...	ACCEPT	Summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important. Reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
GO:0006898 receptor-mediated endocytosis	TAS PMID:9157966 A novel mosaic protein containing LDL receptor elements is h...	ACCEPT	Summary: SorLA mediates AP-2/clathrin-dependent internalization of surface ligands (uPA-PAI1, APOA5, IL6, HER2), feeding them into its endosomal sorting itinerary. Reason: Core uptake step of SorLA's cargo-sorting cycle (IDA/TAS).

📄 View Raw YAML

id: Q92673
gene_symbol: SORL1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  SORL1 encodes sortilin-related receptor, a large type I membrane receptor of the
  VPS10P/LDLR family that cycles through the trans-Golgi network, endosomes, recycling
  endosomes, and the plasma membrane. It binds and sorts cargo proteins and peptides,
  including amyloid precursor protein, amyloid-beta peptides, lipoprotein-related
  ligands, neurotrophic factors and receptors, insulin receptor, and cytokine-receptor
  complexes. In neurons, SORL1 retains and retrieves APP-containing complexes through
  Golgi/endosomal routes and can direct amyloid-beta toward lysosomal degradation,
  thereby reducing amyloidogenic APP processing. Other cargo-specific roles in lipid
  metabolism, trophic signaling, cytokine signaling, vascular smooth muscle behavior,
  and receptor recycling reflect the same receptor-mediated sorting biology in different
  cell contexts.
existing_annotations:
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0006892
    label: post-Golgi vesicle-mediated transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SorLA participates in vesicular transport from the TGN onward, dispatching itself and cargo to endosomes and the cell surface.
    action: ACCEPT
    reason: Core trafficking step in SorLA's sorting itinerary (IBA/IDA).
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system.
    action: ACCEPT
    reason: Correct but generic; consistent with the transmembrane receptor.
- term:
    id: GO:0006622
    label: protein targeting to lysosome
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SorLA routes select cargo (LPL, GDNF, IL6, APOA5, amyloid-beta) to lysosomes for degradation, a defined branch of its sorting output.
    action: ACCEPT
    reason: Core degradative sorting branch of the receptor (IBA/IDA).
- term:
    id: GO:0045053
    label: protein retention in Golgi apparatus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing.
    action: ACCEPT
    reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0005041
    label: low-density lipoprotein particle receptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: SorLA functions as an LDL-receptor-family member with complement-type ligand-binding repeats that bind lipoprotein and LRPAP1/RAP ligands.
    action: ACCEPT
    reason: Core receptor activity defining SorLA's LDLR-family identity.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0005764
    label: lysosome
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: SorLA routes select cargo (LPL, GDNF, APOA5, amyloid-beta) toward lysosomes for catabolism; the lysosome is a destination of its degradative sorting branch.
    action: KEEP_AS_NON_CORE
    reason: Terminal destination compartment downstream of SorLA's sorting decisions.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: SorLA is a single-pass type I membrane protein; only a small RIP-released C-terminal fragment is cytosolic, so a bulk cytosol annotation overstates its distribution.
    action: MARK_AS_OVER_ANNOTATED
    reason: IEA cytosol overstates localization of an integral membrane protein.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting.
    action: ACCEPT
    reason: Membrane localization underpins SorLA's endosomal sorting function.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system.
    action: ACCEPT
    reason: Correct but generic; consistent with the transmembrane receptor.
- term:
    id: GO:0030658
    label: transport vesicle membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SorLA is carried in transport/secretory and endosome-to-TGN retrograde vesicles that shuttle it and its cargo between compartments.
    action: ACCEPT
    reason: 'Vesicle-membrane localization matches its trafficking itinerary (UniProt: retrograde vesicles).'
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval.
    action: ACCEPT
    reason: Membrane sub-localization supporting endosomal cargo sorting.
- term:
    id: GO:0032585
    label: multivesicular body membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: MVB-membrane localization is consistent with SorLA delivering cargo to the lysosomal degradation pathway.
    action: KEEP_AS_NON_CORE
    reason: Late-endosomal membrane, secondary to the core TGN/endosome retrieval role.
- term:
    id: GO:0055038
    label: recycling endosome membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors.
    action: ACCEPT
    reason: Membrane sub-localization for SorLA's recycling function.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11821067
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16174740
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16407538
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17326667
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23333276
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25643321
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26053850
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26858303
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28265003
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30679749
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0002024
    label: diet induced thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA's metabolic regulation of adipose energy expenditure extends to diet-induced thermogenesis, a systemic consequence of its ectodomain activity.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic energy-balance phenotype, downstream of metabolic signaling roles.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed.
    action: UNDECIDED
    reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
- term:
    id: GO:0005771
    label: multivesicular body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: SorLA is seen in MVBs/late endosomes as part of cargo routing toward lysosomal degradation (e.g. LPL, GDNF).
    action: KEEP_AS_NON_CORE
    reason: Downstream late-endosomal station of the degradative arm of SorLA sorting.
- term:
    id: GO:0006605
    label: protein targeting
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role.
    action: ACCEPT
    reason: 'Core process: directing proteins to their correct intracellular location.'
- term:
    id: GO:0010897
    label: negative regulation of triglyceride catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By trafficking LPL to lysosomes and degrading it, SorLA reduces lipase activity and triglyceride catabolism; a metabolic consequence of degradative sorting.
    action: KEEP_AS_NON_CORE
    reason: Lipid-metabolism effect downstream of SorLA-mediated LPL turnover.
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA modulates migration of smooth-muscle and myeloid cells through uPAR/PLAUR surface regulation, a pleiotropic consequence of its receptor trafficking.
    action: KEEP_AS_NON_CORE
    reason: Generic pleiotropic migration role secondary to ligand trafficking.
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition.
    action: MODIFY
    reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation.
    proposed_replacement_terms: &id001
    - id: GO:1902430
      label: negative regulation of amyloid-beta formation
- term:
    id: GO:0030514
    label: negative regulation of BMP signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: The SorLA N-terminal ectodomain inhibits BMP/Smad signaling in adipose tissue to restrain energy expenditure; a metabolic, ectodomain-mediated role.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic metabolic signaling effect of the soluble ectodomain (IEA/ISS).
- term:
    id: GO:0038020
    label: insulin receptor recycling
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA recycles internalized INSR via the Golgi to the surface, raising INSR surface levels in adipocytes; a tissue-specific instance of its recycling-sorting role.
    action: KEEP_AS_NON_CORE
    reason: Cargo-specific recycling event downstream of SorLA's general recycling activity.
- term:
    id: GO:0043025
    label: neuronal cell body
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: SorLA is enriched in neuronal soma, consistent with its high brain expression and role in neuronal cargo (APP, TrkB, GDNF) trafficking.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific localization reflecting neuronal expression, not a distinct core compartment.
- term:
    id: GO:0045053
    label: protein retention in Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing.
    action: ACCEPT
    reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
- term:
    id: GO:0046628
    label: positive regulation of insulin receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By increasing INSR surface expression through recycling, SorLA strengthens insulin signaling in adipose tissue, a pleiotropic downstream consequence.
    action: KEEP_AS_NON_CORE
    reason: Signaling effect secondary to SorLA-mediated INSR recycling.
- term:
    id: GO:0050768
    label: negative regulation of neurogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA influences neuronal development consistent with its high brain expression and trafficking of neurotrophic cargo (BDNF/TrkB, GDNF).
    action: KEEP_AS_NON_CORE
    reason: Developmental role downstream of neurotrophic-receptor sorting (IEA/ISS).
- term:
    id: GO:0097356
    label: perinucleolar compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: No evidence places this transmembrane sorting receptor in the perinucleolar compartment; the IEA call is implausible for SorLA.
    action: MARK_AS_OVER_ANNOTATED
    reason: Implausible nuclear sub-compartment for a membrane sorting receptor; electronic over-annotation.
- term:
    id: GO:0099638
    label: endosome to plasma membrane protein transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA promotes return of internalized receptors (INSR, HER2) from endosomes to the plasma membrane, a recycling arm of its sorting activity.
    action: ACCEPT
    reason: 'Core recycling route mediated by SorLA (UniProt: HER2/INSR recycling).'
- term:
    id: GO:1900168
    label: positive regulation of glial cell-derived neurotrophic factor production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA controls regulated (vs constitutive) GDNF secretion by sorting GDNF and its receptors, influencing GDNF availability; a neurotrophic-specific role.
    action: KEEP_AS_NON_CORE
    reason: Cargo-specific neurotrophic effect downstream of GDNF sorting.
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:1902992
    label: negative regulation of amyloid precursor protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting.
    action: ACCEPT
    reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
- term:
    id: GO:1902997
    label: negative regulation of neurofibrillary tangle assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: SorLA's primary action is on APP/Abeta trafficking; an effect on tau neurofibrillary-tangle assembly is at best indirect and rests only on electronic/ISS inference.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tau-tangle effect is speculative and indirect; electronic over-annotation.
- term:
    id: GO:1904179
    label: positive regulation of adipose tissue development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Through its metabolic actions (INSR recycling, BMP inhibition, LPL turnover) SorLA influences adipose tissue development; a pleiotropic systemic role.
    action: KEEP_AS_NON_CORE
    reason: Systemic metabolic/developmental role secondary to its trafficking functions.
- term:
    id: GO:1990845
    label: adaptive thermogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Soluble SorLA represses adipose thermogenesis via BMP/Smad inhibition, shifting energy balance toward storage; a metabolic role of the ectodomain.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic metabolic phenotype of the shed ectodomain (IEA/ISS).
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: enables
  review:
    summary: "This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface."
    action: ACCEPT
    reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:11294867
  qualifier: enables
  review:
    summary: "This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface."
    action: ACCEPT
    reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: TAS
  original_reference_id: PMID:9157966
  qualifier: enables
  review:
    summary: "This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface."
    action: ACCEPT
    reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:11294867
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:16174740
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:21994944
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:11082041
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:15053742
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:16393139
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: EXP
  original_reference_id: PMID:16531402
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: ER-membrane residence reflects the newly synthesized receptor before propeptide cleavage and export; not where SorLA performs cargo sorting.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic localization, peripheral to the endosome/TGN sorting role.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:11294867
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:14764453
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:15053742
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:31138794
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting.
    action: ACCEPT
    reason: Membrane localization underpins SorLA's endosomal sorting function.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:23333276
  qualifier: located_in
  review:
    summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting.
    action: ACCEPT
    reason: Membrane localization underpins SorLA's endosomal sorting function.
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:17646382
  qualifier: located_in
  review:
    summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval.
    action: ACCEPT
    reason: Membrane sub-localization supporting endosomal cargo sorting.
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval.
    action: ACCEPT
    reason: Membrane sub-localization supporting endosomal cargo sorting.
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:31138794
  qualifier: located_in
  review:
    summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval.
    action: ACCEPT
    reason: Membrane sub-localization supporting endosomal cargo sorting.
- term:
    id: GO:0055038
    label: recycling endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors.
    action: ACCEPT
    reason: Membrane sub-localization for SorLA's recycling function.
- term:
    id: GO:0055038
    label: recycling endosome membrane
  evidence_type: EXP
  original_reference_id: PMID:31138794
  qualifier: located_in
  review:
    summary: Membrane localization to recycling endosomes is consistent with SorLA promoting endocytic recycling of internalized receptors.
    action: ACCEPT
    reason: Membrane sub-localization for SorLA's recycling function.
- term:
    id: GO:0001960
    label: negative regulation of cytokine-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:26858303
  qualifier: involved_in
  review:
    summary: SorLA dampens cytokine signaling by internalizing and degrading IL6/CLCF1-CRLF1-CNTFR complexes, a downstream effect of its endocytic-degradative sorting.
    action: KEEP_AS_NON_CORE
    reason: Signaling modulation secondary to SorLA cargo internalization and turnover.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:26858303
  qualifier: is_active_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0038024
    label: cargo receptor activity
  evidence_type: IDA
  original_reference_id: PMID:26858303
  qualifier: enables
  review:
    summary: "This is SorLA's defining activity: a VPS10P-domain cargo receptor that binds and sorts client proteins (APP, LPL, INSR, HER2, GDNF) among the TGN, endosomes and surface."
    action: ACCEPT
    reason: Core defining molecular function of SorLA as an intracellular sorting receptor.
- term:
    id: GO:1905146
    label: lysosomal protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:26858303
  qualifier: involved_in
  review:
    summary: Lysosomal degradation of SorLA-delivered cargo is a downstream consequence of its degradative sorting branch rather than the proximal sorting activity itself.
    action: KEEP_AS_NON_CORE
    reason: Downstream catabolic outcome of SorLA's lysosomal targeting.
- term:
    id: GO:0031901
    label: early endosome membrane
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: is_active_in
  review:
    summary: SorLA occupies the early-endosome membrane where its cytoplasmic domain recruits sorting adaptors for cargo retrieval.
    action: ACCEPT
    reason: Membrane sub-localization supporting endosomal cargo sorting.
- term:
    id: GO:0042147
    label: retrograde transport, endosome to Golgi
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: involved_in
  review:
    summary: SorLA's cytosolic tail engages retromer (VPS29) and GGA adaptors to retrieve itself and cargo from endosomes back to the TGN.
    action: ACCEPT
    reason: Central retrieval route defining SorLA's sorting behaviour (IDA).
- term:
    id: GO:0140318
    label: protein transporter activity
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: enables
  review:
    summary: SorLA physically carries bound cargo proteins between compartments, consistent with its cargo-receptor role in directing protein localization.
    action: ACCEPT
    reason: Captures the cargo-carrying activity central to SorLA's sorting function (IDA).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:16407538
  qualifier: enables
  review:
    summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition.
    action: MODIFY
    reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation.
    proposed_replacement_terms: *id001
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:17855360
  qualifier: enables
  review:
    summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition.
    action: MODIFY
    reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation.
    proposed_replacement_terms: *id001
- term:
    id: GO:0019828
    label: aspartic-type endopeptidase inhibitor activity
  evidence_type: IMP
  original_reference_id: PMID:21989385
  qualifier: enables
  review:
    summary: SorLA reduces BACE1-dependent APP cleavage by sequestering APP and interfering with BACE1-APP encounter; this is competitive cargo sorting, not direct aspartic-protease inhibition.
    action: MODIFY
    reason: Effect on BACE1 is indirect via trafficking; better captured as negative regulation of amyloid-beta formation.
    proposed_replacement_terms: *id001
- term:
    id: GO:1902992
    label: negative regulation of amyloid precursor protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:16407538
  qualifier: involved_in
  review:
    summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting.
    action: ACCEPT
    reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
- term:
    id: GO:1902992
    label: negative regulation of amyloid precursor protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting.
    action: ACCEPT
    reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
- term:
    id: GO:1902992
    label: negative regulation of amyloid precursor protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21989385
  qualifier: involved_in
  review:
    summary: By retaining APP in the TGN and limiting its access to secretases, SorLA reduces amyloidogenic APP catabolism, the best-characterized physiological output of its sorting.
    action: ACCEPT
    reason: Hallmark functional consequence of SorLA's APP retention (IDA/IMP).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11294867
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:11294867
  qualifier: located_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: IDA
  original_reference_id: PMID:11294867
  qualifier: involved_in
  review:
    summary: SorLA mediates AP-2/clathrin-dependent internalization of surface ligands (uPA-PAI1, APOA5, IL6, HER2), feeding them into its endosomal sorting itinerary.
    action: ACCEPT
    reason: Core uptake step of SorLA's cargo-sorting cycle (IDA/TAS).
- term:
    id: GO:0007218
    label: neuropeptide signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:11294867
  qualifier: involved_in
  review:
    summary: SorLA's interaction with neuropeptides (HA) links it to neuropeptide signaling, a downstream context of its ligand-binding capacity.
    action: KEEP_AS_NON_CORE
    reason: Signaling context downstream of SorLA neuropeptide binding.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:11294867
  qualifier: located_in
  review:
    summary: Surface-exposed SorLA binds ligands (e.g. APP, IL6, uPAR) and mediates their internalization; the surface pool also undergoes ectodomain shedding.
    action: ACCEPT
    reason: Cell-surface presence is required for SorLA receptor-mediated endocytosis (IDA).
- term:
    id: GO:0042923
    label: neuropeptide binding
  evidence_type: IPI
  original_reference_id: PMID:11082041
  qualifier: enables
  review:
    summary: The VPS10P domain binds neuropeptides such as head activator (HA) and neurotensin; a specific partner-binding activity peripheral to the core sorting role.
    action: KEEP_AS_NON_CORE
    reason: Partner-specific ligand binding; ancillary to the defining cargo-receptor activity.
- term:
    id: GO:0042923
    label: neuropeptide binding
  evidence_type: IPI
  original_reference_id: PMID:11294867
  qualifier: enables
  review:
    summary: The VPS10P domain binds neuropeptides such as head activator (HA) and neurotensin; a specific partner-binding activity peripheral to the core sorting role.
    action: KEEP_AS_NON_CORE
    reason: Partner-specific ligand binding; ancillary to the defining cargo-receptor activity.
- term:
    id: GO:0031333
    label: negative regulation of protein-containing complex assembly
  evidence_type: IMP
  original_reference_id: PMID:21989385
  qualifier: involved_in
  review:
    summary: By sequestering APP and modulating BACE1 access, SorLA can limit assembly of processing complexes; an indirect effect of its cargo-binding behaviour.
    action: KEEP_AS_NON_CORE
    reason: Indirect complex-assembly effect downstream of SorLA ligand sequestration (IMP).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21994944
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:21994944
  qualifier: located_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21994944
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:1900168
    label: positive regulation of glial cell-derived neurotrophic factor production
  evidence_type: IDA
  original_reference_id: PMID:21994944
  qualifier: involved_in
  review:
    summary: SorLA controls regulated (vs constitutive) GDNF secretion by sorting GDNF and its receptors, influencing GDNF availability; a neurotrophic-specific role.
    action: KEEP_AS_NON_CORE
    reason: Cargo-specific neurotrophic effect downstream of GDNF sorting.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30448281
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0006605
    label: protein targeting
  evidence_type: IDA
  original_reference_id: PMID:27322061
  qualifier: involved_in
  review:
    summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role.
    action: ACCEPT
    reason: 'Core process: directing proteins to their correct intracellular location.'
- term:
    id: GO:0010897
    label: negative regulation of triglyceride catabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: By trafficking LPL to lysosomes and degrading it, SorLA reduces lipase activity and triglyceride catabolism; a metabolic consequence of degradative sorting.
    action: KEEP_AS_NON_CORE
    reason: Lipid-metabolism effect downstream of SorLA-mediated LPL turnover.
- term:
    id: GO:0038020
    label: insulin receptor recycling
  evidence_type: IDA
  original_reference_id: PMID:27322061
  qualifier: involved_in
  review:
    summary: SorLA recycles internalized INSR via the Golgi to the surface, raising INSR surface levels in adipocytes; a tissue-specific instance of its recycling-sorting role.
    action: KEEP_AS_NON_CORE
    reason: Cargo-specific recycling event downstream of SorLA's general recycling activity.
- term:
    id: GO:0046628
    label: positive regulation of insulin receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:27322061
  qualifier: involved_in
  review:
    summary: By increasing INSR surface expression through recycling, SorLA strengthens insulin signaling in adipose tissue, a pleiotropic downstream consequence.
    action: KEEP_AS_NON_CORE
    reason: Signaling effect secondary to SorLA-mediated INSR recycling.
- term:
    id: GO:1904179
    label: positive regulation of adipose tissue development
  evidence_type: IDA
  original_reference_id: PMID:27322061
  qualifier: involved_in
  review:
    summary: Through its metabolic actions (INSR recycling, BMP inhibition, LPL turnover) SorLA influences adipose tissue development; a pleiotropic systemic role.
    action: KEEP_AS_NON_CORE
    reason: Systemic metabolic/developmental role secondary to its trafficking functions.
- term:
    id: GO:0002024
    label: diet induced thermogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: SorLA's metabolic regulation of adipose energy expenditure extends to diet-induced thermogenesis, a systemic consequence of its ectodomain activity.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic energy-balance phenotype, downstream of metabolic signaling roles.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21385844
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA cycles through endosomes, capturing internalized cargo (APP, LPL, INSR, HER2) for retrieval to the TGN or routing to lysosomes.
    action: ACCEPT
    reason: Endosome is a defining compartment of SorLA's retrieval/sorting itinerary.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing.
    action: ACCEPT
    reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
- term:
    id: GO:0005771
    label: multivesicular body
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA is seen in MVBs/late endosomes as part of cargo routing toward lysosomal degradation (e.g. LPL, GDNF).
    action: KEEP_AS_NON_CORE
    reason: Downstream late-endosomal station of the degradative arm of SorLA sorting.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA transits the ER during biosynthesis and maturation, but its sorting activity acts downstream in the TGN/endosomal system rather than in the ER.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic transit compartment, upstream of and peripheral to the core sorting cycle.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0006605
    label: protein targeting
  evidence_type: IDA
  original_reference_id: PMID:21385844
  qualifier: involved_in
  review:
    summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role.
    action: ACCEPT
    reason: 'Core process: directing proteins to their correct intracellular location.'
- term:
    id: GO:0030514
    label: negative regulation of BMP signaling pathway
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: The SorLA N-terminal ectodomain inhibits BMP/Smad signaling in adipose tissue to restrain energy expenditure; a metabolic, ectodomain-mediated role.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic metabolic signaling effect of the soluble ectodomain (IEA/ISS).
- term:
    id: GO:1990845
    label: adaptive thermogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Soluble SorLA represses adipose thermogenesis via BMP/Smad inhibition, shifting energy balance toward storage; a metabolic role of the ectodomain.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic metabolic phenotype of the shed ectodomain (IEA/ISS).
- term:
    id: GO:0005041
    label: low-density lipoprotein particle receptor activity
  evidence_type: TAS
  original_reference_id: PMID:20005821
  qualifier: enables
  review:
    summary: SorLA functions as an LDL-receptor-family member with complement-type ligand-binding repeats that bind lipoprotein and LRPAP1/RAP ligands.
    action: ACCEPT
    reason: Core receptor activity defining SorLA's LDLR-family identity.
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871506
  qualifier: located_in
  review:
    summary: As a single-pass type I membrane protein, SorLA sits in the Golgi/TGN membrane where it engages adaptors (GGA, AP-1) and retains cargo such as APP.
    action: ACCEPT
    reason: Correct membrane sub-localization for a transmembrane Golgi sorting receptor.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871494
  qualifier: located_in
  review:
    summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting.
    action: ACCEPT
    reason: Membrane localization underpins SorLA's endosomal sorting function.
- term:
    id: GO:0010008
    label: endosome membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8871506
  qualifier: located_in
  review:
    summary: The transmembrane receptor is embedded in the endosomal limiting membrane, where its cytosolic tail binds retromer/GGA adaptors for sorting.
    action: ACCEPT
    reason: Membrane localization underpins SorLA's endosomal sorting function.
- term:
    id: GO:0050768
    label: negative regulation of neurogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: SorLA influences neuronal development consistent with its high brain expression and trafficking of neurotrophic cargo (BDNF/TrkB, GDNF).
    action: KEEP_AS_NON_CORE
    reason: Developmental role downstream of neurotrophic-receptor sorting (IEA/ISS).
- term:
    id: GO:1902997
    label: negative regulation of neurofibrillary tangle assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: SorLA's primary action is on APP/Abeta trafficking; an effect on tau neurofibrillary-tangle assembly is at best indirect and rests only on electronic/ISS inference.
    action: MARK_AS_OVER_ANNOTATED
    reason: Tau-tangle effect is speculative and indirect; electronic over-annotation.
- term:
    id: GO:1902953
    label: positive regulation of ER to Golgi vesicle-mediated transport
  evidence_type: IMP
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: SorLA promotes anterograde ER-to-Golgi transport of cargo, complementing its retrieval activity in establishing correct cargo localization.
    action: ACCEPT
    reason: Trafficking-regulatory role consistent with its sorting function (IMP).
- term:
    id: GO:1902966
    label: positive regulation of protein localization to early endosome
  evidence_type: IMP
  original_reference_id: PMID:22621900
  qualifier: involved_in
  review:
    summary: SorLA drives delivery of cargo into early endosomes en route to retrieval or degradation, an integral step of its sorting cycle.
    action: ACCEPT
    reason: Direct manifestation of SorLA endosomal cargo sorting (IMP).
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IDA
  original_reference_id: PMID:24523320
  qualifier: enables
  review:
    summary: SorLA directly binds amyloid-beta (and APP C99/Abeta40) via its ectodomain, enabling capture of newly produced Abeta for lysosomal clearance.
    action: ACCEPT
    reason: Defining ligand interaction underlying SorLA's anti-amyloidogenic sorting (IDA/IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24001769
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IMP
  original_reference_id: PMID:22621900
  qualifier: located_in
  review:
    summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing.
    action: ACCEPT
    reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
- term:
    id: GO:0005769
    label: early endosome
  evidence_type: IDA
  original_reference_id: PMID:24001769
  qualifier: located_in
  review:
    summary: SorLA reaches early endosomes after internalization and directs cargo such as APOA5 and APP toward retrieval or onward lysosomal routing.
    action: ACCEPT
    reason: Early endosome is an early station of SorLA's sorting itinerary (IDA/IMP).
- term:
    id: GO:0005802
    label: trans-Golgi network
  evidence_type: IDA
  original_reference_id: PMID:24001769
  qualifier: located_in
  review:
    summary: SorLA is predominantly localized to the TGN, the compartment where it retains APP and from which it dispatches cargo to endosomes.
    action: ACCEPT
    reason: "TGN is the principal steady-state site of this sorting receptor (UniProt: 'predominantly in the TGN')."
- term:
    id: GO:0006622
    label: protein targeting to lysosome
  evidence_type: IDA
  original_reference_id: PMID:24523320
  qualifier: involved_in
  review:
    summary: SorLA routes select cargo (LPL, GDNF, IL6, APOA5, amyloid-beta) to lysosomes for degradation, a defined branch of its sorting output.
    action: ACCEPT
    reason: Core degradative sorting branch of the receptor (IBA/IDA).
- term:
    id: GO:0045732
    label: positive regulation of protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:24523320
  qualifier: involved_in
  review:
    summary: By routing clients (LPL, GDNF, IL6, amyloid-beta) to lysosomes, SorLA promotes their catabolism as a downstream output of degradative sorting.
    action: ACCEPT
    reason: Direct outcome of SorLA's lysosomal targeting branch (IDA).
- term:
    id: GO:0055037
    label: recycling endosome
  evidence_type: IMP
  original_reference_id: PMID:22621900
  qualifier: located_in
  review:
    summary: SorLA traffics through recycling endosomes, enabling cargo such as INSR and HER2 to be returned to the cell surface.
    action: ACCEPT
    reason: Recycling-endosome residence supports SorLA-mediated receptor recycling (IMP).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:22621900
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:24001769
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:24523320
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:2001137
    label: positive regulation of endocytic recycling
  evidence_type: IMP
  original_reference_id: PMID:22621900
  qualifier: involved_in
  review:
    summary: SorLA enhances recycling of internalized cargo back to the surface, exemplified by HER2 recycling that sustains PI3K-dependent signaling.
    action: ACCEPT
    reason: Core recycling-promoting activity of the sorting receptor (IMP).
- term:
    id: GO:0001540
    label: amyloid-beta binding
  evidence_type: IPI
  original_reference_id: PMID:16407538
  qualifier: enables
  review:
    summary: SorLA directly binds amyloid-beta (and APP C99/Abeta40) via its ectodomain, enabling capture of newly produced Abeta for lysosomal clearance.
    action: ACCEPT
    reason: Defining ligand interaction underlying SorLA's anti-amyloidogenic sorting (IDA/IPI).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17855360
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed.
    action: UNDECIDED
    reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
- term:
    id: GO:0005641
    label: nuclear envelope lumen
  evidence_type: IDA
  original_reference_id: PMID:21989385
  qualifier: located_in
  review:
    summary: RIP releases a SorLA C-terminal fragment that localizes to the nucleus, but a specific nuclear-envelope-lumen assignment is not clearly supported by the evidence reviewed.
    action: UNDECIDED
    reason: Cannot verify the nuclear-envelope-lumen call; nuclear targeting is only of a cleaved fragment.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: SorLA transits the ER during biosynthesis and maturation, but its sorting activity acts downstream in the TGN/endosomal system rather than in the ER.
    action: KEEP_AS_NON_CORE
    reason: Biosynthetic transit compartment, upstream of and peripheral to the core sorting cycle.
- term:
    id: GO:0006605
    label: protein targeting
  evidence_type: IDA
  original_reference_id: PMID:16407538
  qualifier: involved_in
  review:
    summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role.
    action: ACCEPT
    reason: 'Core process: directing proteins to their correct intracellular location.'
- term:
    id: GO:0006892
    label: post-Golgi vesicle-mediated transport
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: SorLA participates in vesicular transport from the TGN onward, dispatching itself and cargo to endosomes and the cell surface.
    action: ACCEPT
    reason: Core trafficking step in SorLA's sorting itinerary (IBA/IDA).
- term:
    id: GO:0031267
    label: small GTPase binding
  evidence_type: IPI
  original_reference_id: PMID:17855360
  qualifier: enables
  review:
    summary: Reported binding to a small GTPase (e.g. RHOH) is a specific partner interaction not central to SorLA's cargo-sorting mechanism.
    action: KEEP_AS_NON_CORE
    reason: Specific partner binding, peripheral to the core sorting function (IPI).
- term:
    id: GO:0031985
    label: Golgi cisterna
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: located_in
  review:
    summary: IDA localization to Golgi cisternae is consistent with SorLA's residence in the Golgi stack during cargo sorting and retrieval.
    action: ACCEPT
    reason: Cisternal localization refines the core Golgi pool of this sorting receptor.
- term:
    id: GO:0034067
    label: protein localization to Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: By capturing and retrieving cargo to the Golgi/TGN, SorLA establishes the Golgi localization of clients such as APP.
    action: ACCEPT
    reason: Direct consequence of SorLA's retrieval/retention activity (IDA).
- term:
    id: GO:0045053
    label: protein retention in Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: SorLA retains APP (and other cargo) in the TGN, the key event that limits APP's transit to amyloidogenic late-endosomal processing.
    action: ACCEPT
    reason: Defining sorting outcome that links SorLA to reduced amyloidogenesis (IBA/IDA).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IDA
  original_reference_id: PMID:16407538
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:17855360
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:1902430
    label: negative regulation of amyloid-beta formation
  evidence_type: IMP
  original_reference_id: PMID:21989385
  qualifier: involved_in
  review:
    summary: SorLA lowers Abeta40/Abeta42 generation by sequestering APP from amyloidogenic processing and routing Abeta to lysosomes, the basis of its AD-protective role.
    action: ACCEPT
    reason: Central disease-relevant output directly downstream of SorLA APP sorting (IDA/IMP).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: HDA detection of SorLA in exosomes is consistent with proteomic surveys; it is incidental to the receptor's intracellular sorting function.
    action: KEEP_AS_NON_CORE
    reason: High-throughput proteomic localization; not a core functional site.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14764453
  qualifier: enables
  review:
    summary: Bare 'protein binding' (n=21 IPI) records many partner interactions but conveys no specific molecular function for this cargo receptor.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic MF; specific ligand-binding terms already capture SorLA's activity.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:14764453
  qualifier: located_in
  review:
    summary: ADAM17-mediated shedding releases the soluble SorLA ectodomain (sLR11) into the extracellular space, where it acts as a secreted ligand-binding fragment.
    action: KEEP_AS_NON_CORE
    reason: Reflects shed soluble ectodomain, a secondary product of the membrane receptor.
- term:
    id: GO:0014910
    label: regulation of smooth muscle cell migration
  evidence_type: IDA
  original_reference_id: PMID:14764453
  qualifier: involved_in
  review:
    summary: The shed SorLA ectodomain promotes smooth-muscle migration via increased uPAR surface display, a pleiotropic vascular role of the soluble fragment.
    action: KEEP_AS_NON_CORE
    reason: Vascular phenotype downstream of ectodomain/uPAR handling, not core sorting.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IDA
  original_reference_id: PMID:14764453
  qualifier: located_in
  review:
    summary: Generic membrane association reflects SorLA's nature as an integral single-pass type I membrane protein distributed across the secretory/endosomal system.
    action: ACCEPT
    reason: Correct but generic; consistent with the transmembrane receptor.
- term:
    id: GO:0005768
    label: endosome
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: located_in
  review:
    summary: SorLA cycles through endosomes, capturing internalized cargo (APP, LPL, INSR, HER2) for retrieval to the TGN or routing to lysosomes.
    action: ACCEPT
    reason: Endosome is a defining compartment of SorLA's retrieval/sorting itinerary.
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IDA
  original_reference_id: PMID:16174740
  qualifier: located_in
  review:
    summary: SorLA resides in the Golgi where, with AP-1, it executes TGN-endosome sorting; a major steady-state pool of the receptor is Golgi-associated.
    action: ACCEPT
    reason: Golgi is a core compartment for SorLA's cargo-sorting cycle (UniProt subcellular location).
- term:
    id: GO:0006605
    label: protein targeting
  evidence_type: IMP
  original_reference_id: PMID:16174740
  qualifier: involved_in
  review:
    summary: SorLA directs bound client proteins to specific destinations (TGN retention, lysosomal degradation or surface recycling), the essence of its sorting role.
    action: ACCEPT
    reason: 'Core process: directing proteins to their correct intracellular location.'
- term:
    id: GO:0030169
    label: low-density lipoprotein particle binding
  evidence_type: IPI
  original_reference_id: PMID:17326667
  qualifier: enables
  review:
    summary: Through its LDLR-class complement repeats SorLA binds LDL particles, reflecting its membership in the LDL-receptor gene family.
    action: ACCEPT
    reason: Direct ligand-binding activity characteristic of this LDLR-family receptor (IPI).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:9157966
  qualifier: located_in
  review:
    summary: A minor surface pool of SorLA captures extracellular ligands and undergoes AP-2-dependent endocytosis; surface levels are low but functionally important.
    action: ACCEPT
    reason: Cell-surface localization is the entry point for SorLA's endocytic sorting cycle.
- term:
    id: GO:0006898
    label: receptor-mediated endocytosis
  evidence_type: TAS
  original_reference_id: PMID:9157966
  qualifier: involved_in
  review:
    summary: SorLA mediates AP-2/clathrin-dependent internalization of surface ligands (uPA-PAI1, APOA5, IL6, HER2), feeding them into its endosomal sorting itinerary.
    action: ACCEPT
    reason: Core uptake step of SorLA's cargo-sorting cycle (IDA/TAS).
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: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: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:11082041
  title: Ectodomain shedding, translocation and synthesis of SorLA are stimulated by its ligand head activator.
  findings: []
- id: PMID:11294867
  title: Activation and functional characterization of the mosaic receptor SorLA/LR11.
  findings: []
- id: PMID:11821067
  title: The sorLA cytoplasmic domain interacts with GGA1 and -2 and defines minimum requirements for GGA binding.
  findings: []
- id: PMID:14764453
  title: LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration.
  findings: []
- id: PMID:15053742
  title: The mosaic receptor sorLA/LR11 binds components of the plasminogen-activating system and platelet-derived growth factor-BB similarly to LRP1 (low-density lipoprotein receptor-related protein), but mediates slow internalization of bound ligand.
  findings: []
- id: PMID:16174740
  title: Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports SORL1 as an APP sorting receptor that reduces amyloidogenic peptide formation.
- id: PMID:16393139
  title: Tumour necrosis factor alpha-converting enzyme mediates ectodomain shedding of Vps10p-domain receptor family members.
  findings: []
- id: PMID:16407538
  title: Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports the trafficking mechanism by which SORL1 prevents BACE-APP interactions rather than directly inhibiting BACE catalysis.
- id: PMID:16531402
  title: SorLA signaling by regulated intramembrane proteolysis.
  findings: []
- id: PMID:17326667
  title: Apolipoprotein A-V interaction with members of the low density lipoprotein receptor gene family.
  findings: []
- id: PMID:17646382
  title: Sorting by the cytoplasmic domain of the amyloid precursor protein binding receptor SorLA.
  findings: []
- id: PMID:17855360
  title: SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports SORL1 retention of APP in trans-Golgi compartments through GGA/PACS-1-dependent routing.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
- id: PMID:20005821
  title: Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance.
  findings: []
- id: PMID:21385844
  title: SorLA regulates the activity of lipoprotein lipase by intracellular trafficking.
  findings: []
- id: PMID:21989385
  title: Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.
  findings: []
- id: PMID:21994944
  title: Sorting protein-related receptor SorLA controls regulated secretion of glial cell line-derived neurotrophic factor.
  findings: []
- id: PMID:22621900
  title: GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-β production.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports LR11/SORL1 endocytic trafficking as a regulator of APP intracellular distribution and amyloid-beta levels.
- id: PMID:23333276
  title: SorLA controls neurotrophic activity by sorting of GDNF and its receptors GFRα1 and RET.
  findings: []
- id: PMID:24001769
  title: SORLA-dependent and -independent functions for PACS1 in control of amyloidogenic processes.
  findings: []
- id: PMID:24523320
  title: Lysosomal sorting of amyloid-β by the SORLA receptor is impaired by a familial Alzheimer's disease mutation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract/title verified; supports SORL1 amyloid-beta binding through the VPS10P domain and lysosomal targeting of nascent amyloid-beta peptides.
- id: PMID:25643321
  title: Structural basis for amyloidogenic peptide recognition by sorLA.
  findings: []
- id: PMID:26053850
  title: The Golgi-Localized γ-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid-β Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1).
  findings: []
- id: PMID:26858303
  title: Cytokine-Like Factor 1, an Essential Facilitator of Cardiotrophin-Like Cytokine:Ciliary Neurotrophic Factor Receptor α Signaling and sorLA-Mediated Turnover.
  findings: []
- id: PMID:27322061
  title: SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity.
  findings: []
- id: PMID:28265003
  title: SorLA in Interleukin-6 Signaling and Turnover.
  findings: []
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease networks.
  findings: []
- id: PMID:30448281
  title: Soluble LR11 competes with amyloid β in binding to cerebrospinal fluid-high-density lipoprotein.
  findings: []
- id: PMID:30679749
  title: HSPA12A targets the cytoplasmic domain and affects the trafficking of the Amyloid Precursor Protein receptor SorLA.
  findings: []
- id: PMID:31138794
  title: SORLA regulates endosomal trafficking and oncogenic fitness of HER2.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  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:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:9157966
  title: A novel mosaic protein containing LDL receptor elements is highly conserved in humans and chickens.
  findings: []
- id: Reactome:R-HSA-8871494
  title: SORL1 binds APP(18-770)
  findings: []
- id: Reactome:R-HSA-8871506
  title: SORL1 transports APP(18-770) from endosome lumen to Golgi lumen
  findings: []
core_functions:
- molecular_function:
    id: GO:0038024
    label: cargo receptor activity
  description: >-
    SORL1/SORLA is a type I membrane cargo receptor that binds APP and other ligands
    and routes them through trans-Golgi, endosomal, recycling, lysosomal, and plasma-membrane
    pathways via adaptor-dependent sorting.
  directly_involved_in:
  - id: GO:0006605
    label: protein targeting
  - id: GO:0045053
    label: protein retention in Golgi apparatus
  - id: GO:0042147
    label: retrograde transport, endosome to Golgi
  - id: GO:0006898
    label: receptor-mediated endocytosis
  - id: GO:2001137
    label: positive regulation of endocytic recycling
  locations:
  - id: GO:0005802
    label: trans-Golgi network
  - id: GO:0000139
    label: Golgi membrane
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0031901
    label: early endosome membrane
  - id: GO:0055038
    label: recycling endosome membrane
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:16174740
    supporting_text: >-
      sorLA acts as a sorting receptor that protects APP from processing into Abeta
      and thereby reduces the burden of amyloidogenic peptide formation
  - reference_id: PMID:17855360
    supporting_text: >-
      sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi
      network, preventing release of the precursor into regular processing pathways
  - reference_id: PMID:16407538
    supporting_text: >-
      sorLA acts as a trafficking receptor that prevents BACE-APP interactions and
      hence BACE cleavage of APP
- molecular_function:
    id: GO:0001540
    label: amyloid-beta binding
  description: >-
    SORL1 binds amyloid-beta peptides through its VPS10P domain and can route nascent
    amyloid-beta toward lysosomal catabolism, complementing its APP-retention role
    in lowering amyloidogenic peptide production.
  directly_involved_in:
  - id: GO:0006622
    label: protein targeting to lysosome
  - id: GO:0045732
    label: positive regulation of protein catabolic process
  - id: GO:1902430
    label: negative regulation of amyloid-beta formation
  - id: GO:1902992
    label: negative regulation of amyloid precursor protein catabolic process
  locations:
  - id: GO:0005802
    label: trans-Golgi network
  - id: GO:0010008
    label: endosome membrane
  - id: GO:0031901
    label: early endosome membrane
  supported_by:
  - reference_id: PMID:24523320
    supporting_text: >-
      this receptor to direct lysosomal targeting of nascent Aβ peptides
  - reference_id: PMID:24523320
    supporting_text: >-
      Aβ binds to the amino-terminal VPS10P domain of SORLA
  - reference_id: PMID:22621900
    supporting_text: >-
      LR11 modulates Aβ levels by promoting APP traffic to the endocytic recycling
      compartment
proposed_new_terms: []
suggested_questions:
- question: >-
    Should GO add a more specific APP/amyloid-beta cargo sorting receptor activity
    term for SORL1-like receptor functions, or is cargo receptor activity plus cargo-specific
    binding/process annotations sufficient?
  experts:
  - GO receptor activity curators
  - Alzheimer trafficking experts
- question: >-
    Which SORL1 cargo-specific phenotypes, such as insulin receptor recycling, GDNF/GFRA1
    turnover, IL6-family cytokine regulation, or HER2 recycling, should be retained
    as non-core versus represented only through generic cargo sorting?
  experts:
  - VPS10P-domain receptor experts
  - GO annotation curators
- question: >-
    Are nuclear-envelope or perinucleolar localization annotations for SORL1 supported
    by direct full-text evidence, or are they artifacts of perinuclear Golgi/endosomal
    localization descriptions?
  experts:
  - cellular trafficking curators
  - SORL1 cell biology experts
suggested_experiments:
- description: >-
    Use endogenous SORL1 knock-in/knockout neurons to compare APP, BACE1, and nascent
    amyloid-beta routing across TGN, early endosome, recycling endosome, and lysosomal
    compartments.
  hypothesis: >-
    SORL1 lowers amyloidogenic processing primarily by retaining or retrieving APP/BACE1-containing
    cargo away from compartments that favor BACE cleavage and by routing nascent amyloid-beta
    to lysosomes.
  experiment_type: live-cell cargo trafficking and compartment-resolved APP processing assay
- description: >-
    Introduce Alzheimer-associated SORL1 variants into the endogenous locus and assay
    cargo binding, adaptor recruitment, endosome-to-Golgi retrieval, and A-beta lysosomal
    targeting.
  hypothesis: >-
    Pathogenic SORL1 variants impair specific cargo-binding or adaptor-dependent trafficking
    steps without eliminating the general sorting-receptor scaffold.
  experiment_type: endogenous variant knock-in functional rescue assay
- description: >-
    Compare APP/A-beta, insulin receptor, GDNF/GFRA1, IL6-family cytokine complexes,
    and HER2 as parallel cargoes in matched cellular systems.
  hypothesis: >-
    SORL1 uses a shared trafficking architecture for many cargoes, but Alzheimer-relevant
    APP/A-beta handling depends on cargo-specific binding and adaptor requirements.
  experiment_type: multi-cargo receptor sorting assay

Gene Description

Existing Annotations Review

Core Functions

SORL1/SORLA is a type I membrane cargo receptor that binds APP and other ligands and routes them through trans-Golgi, endosomal, recycling, lysosomal, and plasma-membrane pathways via adaptor-dependent sorting.

SORL1 binds amyloid-beta peptides through its VPS10P domain and can route nascent amyloid-beta toward lysosomal catabolism, complementing its APP-retention role in lowering amyloidogenic peptide production.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

SORL1 notes

Review status

Functional synthesis

Annotation decisions

Knowledge gaps and experiments

2026-06-20 Second-Pass Review Notes

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