id: MODULE:reelin_signaling title: Reelin signaling — RELN binding to VLDLR/LRP8, SRC-family phosphorylation of DAB1, PI3K and LIS1 effector branches, and CRL5(SOCS7) degradation of phospho-DAB1; RELN/VLDLR/LRP8/DAB1/FYN/SRC/PIK3R1/PAFAH1B1/SOCS7/CUL5/RNF7 description: >- Reelin (RELN) is a large secreted glycoprotein made by Cajal-Retzius cells in the marginal zone of the developing cortex and by other neurons later in life. It controls where radially migrating neurons stop and so sets up the layers of the cerebral cortex, hippocampus and cerebellum. Reelin binds the ectodomains of two lipoprotein receptors of the LDL receptor family, the very-low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2, LRP8), and clusters them. The cytoplasmic tails of both receptors carry an NPxY motif bound by the phosphotyrosine-binding domain of the adaptor Disabled-1 (DAB1). Receptor clustering brings DAB1 molecules together at the inner face of the plasma membrane, where the Src-family kinases FYN and SRC phosphorylate DAB1 on tyrosines; phosphorylated DAB1 in turn activates more Src-family kinase, giving a positive feedback loop. Tyrosine-phosphorylated DAB1 is a docking hub for downstream effectors. It binds the p85-alpha regulatory subunit (PIK3R1) of class IA phosphoinositide 3-kinase, which activates AKT and inhibits GSK3B; and it binds LIS1 (PAFAH1B1), the dynein regulator mutated in lissencephaly, linking the Reelin signal to the microtubule machinery of neuronal migration. Phosphorylated DAB1 is also the substrate of the signal's own off-switch. The substrate adaptor SOCS7 recognises phospho-DAB1 and recruits it to a cullin-5 RING ubiquitin ligase (CUL5 with the RING protein RNF7/RBX2 and the Elongin B/C adaptor), which polyubiquitinates DAB1 for proteasomal degradation and so stops neurons at their target layer. In the adult brain the same receptor-DAB1-kinase core modulates NMDA and AMPA receptor function at excitatory synapses and enhances long-term potentiation. Loss of RELN, of DAB1, or of both receptors produces the reeler phenotype in mice, and RELN mutations cause lissencephaly with cerebellar hypoplasia in humans. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000388 title: reelin signaling pathway statement: >- The module boundary follows the RGD Pathway Ontology term and its interactive diagram. The diagram draws Reln associated with Vldlr, Lrp8, Itga3 and Itgb1; Dab1 associated with Vldlr, Lrp8, PAFAH1B1, PtdIns4P and Gria1; reciprocal Fyn/Src-related kinase and Dab1 activation edges; Pik3r1 positively affecting the PI3K-Akt pathway; PAFAH1B1 positively affecting neuronal migration and brain development; Grin2a/Grin2b associated with the receptors and driving Ca2+ entry; and Pafah1b2/Pafah1b3 associated with Vldlr. The record text adds Reelin processing, receptor clustering, and phosphorylation-dependent ubiquitination of Dab1 as fine tuning. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000388.yaml). - source_id: GO:0038026 title: reelin-mediated signaling pathway statement: >- The GO mapping recorded for PW:0000388 in the project's module seeds (skos:relatedMatch, from the PW definition cross-reference). It is the module's process concept. - source_id: gomodel:66187e4700002704 title: Inhibition of reelin signaling via ubiquitination and degradation of DAB1 by the ECS(SOCS7) complex in the cortical plate of the developing cerebral cortex (Human). statement: >- Independent curator-built human GO-CAM (cached under gocams/66187e4700002704/) and the project's best-overlap model for PW:0000388. It chains RELN receptor ligand activity -> LRP8 reelin receptor activity -> FYN protein tyrosine kinase activity (input DAB1) -> DAB1 signaling adaptor activity, all part of GO:0038026, and FYN -> SOCS7 ubiquitin-like ligase-substrate adaptor activity -> RNF7 ubiquitin protein ligase activity, which directly negatively regulates DAB1, with CUL5 ubiquitin ligase complex scaffold activity. The termination part of this module is taken from it. - source_id: gomodel:66187e4700002778 title: The reelin signaling pathway (Human). statement: >- The companion human GO-CAM models the same RELN -> LRP8 -> FYN -> DAB1 chain without the CRL5 termination arm. - source_id: PMID:10571240 title: Reelin is a ligand for lipoprotein receptors. statement: Reelin binds VLDLR and ApoER2 directly; these are the core receptors. supporting_text: Reelin binds directly to lipoprotein receptors, preferably the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). - source_id: PMID:10380922 title: Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. statement: >- Double receptor knockouts phenocopy reeler and Dab1 mutants, placing the two receptors and DAB1 in one linear pathway. supporting_text: Inversion of cortical layers and absence of cerebellar foliation in these animals precisely mimic the phenotype of mice lacking Reelin or mDab1. - source_id: PMID:17974915 title: Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development. statement: >- Reelin-induced, phosphorylation-dependent DAB1 degradation by Cul5-SOCS complexes is the pathway's negative feedback, so it is modelled as a part of the module rather than as external regulation. supporting_text: degradation of Dab1 depends on Dab1 phosphorylation at specific tyrosine residues and on the E3 ubiquitin ligase component Cullin 5 (Cul5) - source_id: PMID:16148228 title: Reelin modulates NMDA receptor activity in cortical neurons. statement: >- Supports treating NMDA receptor subunits as downstream targets rather than participants: the receptor is phosphorylated and potentiated by the Reelin-DAB1-SFK core, which it does not itself carry. supporting_text: Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons - source_id: PMID:16102539 title: Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. statement: >- ApoER2 associates with NMDA receptors at the postsynaptic density, and an alternatively spliced ApoER2 exon is needed for Reelin-induced NMDA receptor subunit phosphorylation; the NMDA receptor is again the object acted on. supporting_text: This exon is alternatively spliced in an activity-dependent manner and is required for Reelin-induced tyrosine phosphorylation of NMDA receptor subunits. - source_id: PMID:10939329 title: Reelin binds alpha3beta1 integrin and inhibits neuronal migration. statement: >- The basis for RGD's Itga3/Itgb1-Reln edges. Recorded as context and as a knowledge gap, not as a receptor part (see notes, boundary decision 5). supporting_text: Recombinant and native Reelin associate with alpha3beta1 integrin, which regulates neuron-glia interactions and is required to achieve proper laminar organization. notes: >- Derived from the RGD Pathway Ontology diagram PW:0000388 through the RGD_PATHWAY_ONTOLOGY project's diagram->module route. RGD curates 15 human genes to PW:0000388 (DAB1 FYN GRIA1 GRIN2A GRIN2B ITGA3 ITGB1 LRP8 PAFAH1B1 PAFAH1B2 PAFAH1B3 PIK3R1 RELN SRC VLDLR). Nine of them are modelled as participants here (RELN, VLDLR, LRP8, DAB1, FYN, SRC, PIK3R1, PAFAH1B1, plus the downstream AKT step by reference), and three gene products not on the RGD list (SOCS7, CUL5, RNF7) are added for signal termination. Molecular functions were chosen from each protein's experimental GO annotations in QuickGO (October 2026) and, where a gene review exists, from its core functions: LRP8 reelin receptor activity GO:0038025 (core function in the LRP8 review); VLDLR reelin receptor activity GO:0038025 (mouse Vldlr IDA/IGI/IMP, human ISS; VLDLR has no gene review yet); FYN and SRC non-membrane spanning protein tyrosine kinase activity GO:0004715 (IDA for both; core function in the SRC review; the GO-CAMs use the parent GO:0004713); DAB1 signaling adaptor activity GO:0035591 (ISS/IEA only, as in both GO-CAMs; DAB1 has no experimental MF row in human GOA and no gene review); PIK3R1 1-phosphatidylinositol-3-kinase regulator activity GO:0046935 (core in the PIK3R1 review); PAFAH1B1 cytoskeletal motor regulator activity GO:0140659 (core in the PAFAH1B1 review); SOCS7 ubiquitin-like ligase-substrate adaptor activity GO:1990756 (ISS, as in the GO-CAM); CUL5 ubiquitin ligase complex scaffold activity GO:0160072 (IDA); RNF7 ubiquitin protein ligase activity GO:0061630 (IDA). RELN carries receptor ligand activity GO:0048018, as in both GO-CAMs and accepted in the RELN review, whose core function is the sibling-branch lipoprotein particle receptor binding GO:0070325; the ligand role is the activity that matters to this module, so the GO-CAM term is used and the core-coverage warning this produces is expected. Comparator check for the boundary (CLAUDE.md, "do not add what curators deliberately declined to add"). QuickGO annotations to GO:0038026 or its child GO:0038025 in human, mouse and rat (October 2026) are carried by RELN, VLDLR, LRP8, DAB1, FYN, PAFAH1B1, CUL5, RNF7, CRK, CRKL, FKRP and STAT5A. None is carried by GRIN2A, GRIN2B, GRIA1, ITGA3, ITGB1, PAFAH1B2 or PAFAH1B3, and, notably, none by SRC or PIK3R1 either. Boundary decisions. (1) SRC is kept as a participant despite lacking GO:0038026, because the double Fyn/Src knockout almost abolishes Dab1 tyrosine phosphorylation and phenocopies dab1 mutants (PMID:16162939), and SRC itself performs the step (phosphorylating DAB1), which is participation, not substrate status. FYN is the main kinase and SRC the redundant one. The SRC GO:0038026 absence looks like a curation gap, not a convention, given that FYN carries the term by IDA in mouse. (2) PIK3R1 is kept for the same reason: Reelin triggers DAB1 binding to p85-alpha, and PI3K activity is required for Reelin-dependent cortical plate formation (PMID:12882964). Its PI3K -> PIP3 -> AKT continuation is not re-modelled; it is included by reference (module_ref) to pi3k_akt_mtor#akt_activation, the AKT step of the generic PI3K-AKT-mTOR module, which is also how RGD draws it (Pik3r1 --+> the PI3K-Akt subpathway PW:0000232). PW:0000232 is therefore mentioned here but not listed as an evidence source, since this module does not cover that pathway. (3) PAFAH1B1 (LIS1) is a participant: it binds phospho-DAB1 in a Reelin-induced manner and genetically interacts with the pathway (PMID:14578885), and it carries GO:0038026 by IMP in mouse. Its activity in this module is its regulation of dynein (GO:0140659), the activity that moves the nucleus during migration; the nucleokinesis module (modules/nucleokinesis.yaml) is the downstream neighbour that models that machinery and treats Reelin signalling as upstream. (4) PAFAH1B2 and PAFAH1B3 are excluded. They are the catalytic alpha2/alpha1 subunits of the platelet-activating factor acetylhydrolase IB heterotrimer (PAF-AH, EC 3.1.1.47), LIS1's partners in that enzyme. RGD draws them only as associated with Vldlr (Zhang et al., PLoS One 2007, an RGD reference). They carry no reelin-pathway annotation in any of the three species, they have no gene reviews, and the reported link is a single binding study. No step of the Reelin signal needs their phospholipase activity. They are recorded as candidate modulators to revisit if receptor binding is confirmed. (5) ITGA3/ITGB1 (alpha3beta1 integrin) are context, not participants. Reelin was reported to bind alpha3beta1, and loss of alpha3beta1 lowers Dab1 levels (PMID:10939329), but later work established VLDLR and ApoER2 as the receptors that are necessary and sufficient for Dab1 phosphorylation (the double receptor knockout is reeler-like, PMID:10380922), and Benhayon et al. explicitly list integrin and protocadherin as proposed alternative receptors (PMID:12670700). Curators have not annotated either integrin to GO:0038026, and neither GO-CAM includes them. RGD's integrin edges point at the separate integrin-mediated signaling subpathway PW:0000286, which is modelled in modules/integrin_fak_src_signaling.yaml; PW:0000286 is therefore mentioned here but not listed as an evidence source. (6) GRIN2A, GRIN2B and GRIA1 are excluded as downstream targets. In the adult, Reelin acting through ApoER2, DAB1 and Src-family kinases causes tyrosine phosphorylation of NMDA receptor subunits and potentiates Ca2+ influx through them (PMID:16148228, PMID:16102539); RGD also draws a PI3K route to AMPA receptors (GRIA1; Qiu et al., J Neurosci 2006, an RGD reference not cached here). In both cases the glutamate receptor is the object the pathway acts on (the kinase substrate, or the channel whose activity or trafficking is modulated), not a protein that carries the Reelin signal: it binds no Reelin, recruits no DAB1 and phosphorylates nothing. Applying the substrate-vs-participant rule, they are outputs of the module, as SREBP target genes are outputs of the SREBP module. The comparator agrees: none of the three carries GO:0038026. The adult synaptic arm is recorded in prose and as a knowledge gap, and should become a separate module (Reelin modulation of glutamatergic synaptic plasticity) built on the ionotropic glutamate receptor modules once those exist. (7) The termination arm is added from the human GO-CAM gomodel:66187e4700002704 and the primary papers (PMID:14645539, PMID:17974915, PMID:24210661). ELOB and ELOC, the Elongin B/C adaptor that links SOCS box proteins to CUL5, are obligate members of this ECS complex but are not modelled as separate annotons, following the GO-CAM, which also omits them; both have gene reviews. (8) Other branches not on the RGD diagram are left out of this draft: CRK/CRKL binding to phospho-DAB1 and activation of RAPGEF1 (C3G)/RAP1, which are annotated to GO:0038026 by IGI/IMP in mouse and are a strong candidate for a further effector part; the cadherin-related neuronal receptors (protocadherins), which the RGD text mentions as alternative Reelin receptors; and the Reelin-regulated transcription factor STAT5A. Competing receptor ligands (APOE, LRPAP1/RAP), Reelin proteolytic processing, and transcriptional control of RELN by TBR1, CASK and thyroid hormone are upstream regulation, not parts. GO-CAM and GOA observations for upstream review. Neither human GO-CAM includes VLDLR, although VLDLR is a co-equal Reelin receptor with GO:0038025 annotations. Both models enable LRP8 activity with isoform UniProtKB:Q14114-4 but take LRP8 (canonical Q14114) as RELN's input; this module grounds LRP8 on the canonical accession. In gomodel:66187e4700002704 the FYN activity and its causal edges cite PMID:16979591, a study of Src-family phosphorylation of Nogo-A that does not address Reelin or DAB1, and CUL5's process and causal edge cite PMID:34518685, a CUL5-ARIH2 structure paper that also does not address DAB1; the Reelin-specific evidence is PMID:17974915 and PMID:24210661. In GOA, CUL5 and RNF7 carry GO:0038026 but SOCS7 does not. Gene reviews exist for RELN, LRP8, SRC, PIK3R1 and PAFAH1B1; VLDLR, DAB1, FYN, SOCS7, CUL5 and RNF7 have none, and PANTHER family ids and PTNs are deliberately not asserted. module: id: reelin_signaling label: Reelin signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: reelin-mediated signaling pathway term: id: GO:0038026 label: reelin-mediated signaling pathway description: >- Signalling initiated by Reelin binding to VLDLR and ApoER2 and transmitted through DAB1 tyrosine phosphorylation. This is the GO term mapped to PW:0000388. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cellular_components: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol parts: - order: 1 role: Reelin binding to and clustering of its lipoprotein receptors node: id: reelin_receptor_binding label: RELN binding to VLDLR and LRP8 (ApoER2) module_type: REGULATORY_STEP description: >- Secreted Reelin, acting as an oligomer, binds the ectodomains of VLDLR and ApoER2 in a calcium-dependent manner and clusters them. The two receptors are partly redundant: loss of either gives a mild defect and loss of both a reeler phenotype. annotons: - id: reln_ligand label: RELN receptor ligand activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RELN term: id: UniProtKB:P78509 label: Reelin function: preferred_term: receptor ligand activity term: id: GO:0048018 label: receptor ligand activity targets: - preferred_term: VLDLR term: id: UniProtKB:P98155 label: Very low-density lipoprotein receptor - preferred_term: LRP8 (ApoER2) term: id: UniProtKB:Q14114 label: Low-density lipoprotein receptor-related protein 8 locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Extracellular positional cue secreted by Cajal-Retzius cells; binds and clusters both receptors. evidence: - source_id: PMID:10571240 statement: Reelin binding to the receptors needs calcium and is blocked by apoE. supporting_text: Binding requires calcium, and it is inhibited in the presence of apoE. - source_id: PMID:10571241 statement: Reelin binds both receptor ectodomains directly. supporting_text: Reelin binds directly and specifically to the ectodomains of VLDLR and ApoER2 in vitro gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002705 title: RELN receptor ligand activity (GO:0048018), part of GO:0038026 - model: gomodel:66187e4700002778 activity: gomodel:66187e4700002778/66187e4700002779 title: RELN receptor ligand activity (GO:0048018), part of GO:0038026 - id: lrp8_reelin_receptor label: LRP8 (ApoER2) reelin receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LRP8 term: id: UniProtKB:Q14114 label: Low-density lipoprotein receptor-related protein 8 function: preferred_term: reelin receptor activity term: id: GO:0038025 label: reelin receptor activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The higher-affinity Reelin receptor; its NPxY tail binds DAB1. Loss of ApoER2 has the stronger effect on cortical layering and Dab1 phosphorylation. evidence: - source_id: PMID:12670700 statement: Purified Reelin binds ApoER2 more readily than VLDLR, and ApoER2 loss reduces Dab1 phosphorylation more. supporting_text: Purified Reelin associated more readily with ApoER2 than with VLDLR and no synergy was observed in the presence of both receptors. - source_id: PMID:10380922 statement: Both receptors bind DAB1 on their cytoplasmic tails. supporting_text: Both receptors can bind mDab1 on their cytoplasmic tails gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002716 title: LRP8 reelin receptor activity (GO:0038025), part of GO:0038026 - model: gomodel:66187e4700002778 activity: gomodel:66187e4700002778/66187e4700002790 title: LRP8 reelin receptor activity (GO:0038025), part of GO:0038026 - id: vldlr_reelin_receptor label: VLDLR reelin receptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: VLDLR term: id: UniProtKB:P98155 label: Very low-density lipoprotein receptor function: preferred_term: reelin receptor activity term: id: GO:0038025 label: reelin receptor activity locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- The second Reelin receptor, partly redundant with ApoER2; after binding Reelin it internalizes it. Not in either human GO-CAM. evidence: - source_id: PMID:10571240 statement: VLDLR binds and internalizes Reelin. supporting_text: After binding to VLDLR on the cell surface, Reelin is internalized into vesicles. - source_id: PMID:10571241 statement: Blocking VLDLR and ApoER2 abolishes Reelin-induced Dab1 phosphorylation. supporting_text: blockade of VLDLR and ApoER2 correlates with loss of Reelin-induced tyrosine phosphorylation of Disabled-1 in cultured primary embryonic neurons - order: 2 role: DAB1 recruitment and Src-family kinase tyrosine phosphorylation node: id: dab1_phosphorylation label: SRC-family kinase phosphorylation of receptor-bound DAB1 module_type: REACTION description: >- DAB1 bound to the clustered receptor tails at the plasma membrane is tyrosine-phosphorylated by FYN and, redundantly, SRC. Phospho-DAB1 further activates the kinases, a positive feedback loop that amplifies the signal. annotons: - id: dab1_adaptor label: DAB1 signaling adaptor activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: DAB1 term: id: UniProtKB:O75553 label: Disabled homolog 1 function: preferred_term: signaling adaptor activity term: id: GO:0035591 label: signaling adaptor activity locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- Binds the receptor NPxY tails and membrane phosphoinositides through its PTB domain; once tyrosine-phosphorylated it activates Src-family kinases and docks the downstream effectors (PI3K p85-alpha, LIS1) and the SOCS7 degradation adaptor. evidence: - source_id: PMID:12882964 statement: The DAB1 PTB domain binds receptor tails and membrane lipids, so DAB1 is phosphorylated at the plasma membrane. supporting_text: Because the Dab1 phosphotyrosine binding domain can interact simultaneously with membrane lipids and with the intracellular domains of apolipoprotein E receptor 2 and very low density lipoprotein receptor, Dab1 is preferentially recruited to the neuronal plasma membrane, where it is phosphorylated. - source_id: PMID:12526740 statement: Phospho-DAB1 is both a substrate and an activator of Src-family kinases. supporting_text: Dab1 is a physiological substrate as well as an activator of SFKs in neurons. gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002736 title: DAB1 signaling adaptor activity (GO:0035591), part of GO:0038026 - model: gomodel:66187e4700002778 activity: gomodel:66187e4700002778/66187e4700002810 title: DAB1 signaling adaptor activity (GO:0035591), part of GO:0038026 - id: fyn_dab1_kinase label: FYN tyrosine phosphorylation of DAB1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: FYN term: id: UniProtKB:P06241 label: Tyrosine-protein kinase Fyn function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity targets: - preferred_term: DAB1 term: id: UniProtKB:O75553 label: Disabled homolog 1 locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: The principal DAB1 kinase in the developing brain. evidence: - source_id: PMID:12526739 statement: Src-family kinase inhibitors block Reelin-induced Dab1 phosphorylation, and Fyn is required for normal Dab1 levels and phosphorylation. supporting_text: fyn is required for proper Dab1 levels and phosphorylation in vivo and in vitro. - source_id: PMID:12526740 statement: Reelin activates Src-family kinases through its receptors and Dab1. supporting_text: Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1. gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002727 title: FYN protein tyrosine kinase activity (GO:0004713) with input DAB1, part of GO:0038026 - model: gomodel:66187e4700002778 activity: gomodel:66187e4700002778/66187e4700002801 title: FYN protein tyrosine kinase activity (GO:0004713), part of GO:0038026 - id: src_dab1_kinase label: SRC tyrosine phosphorylation of DAB1 (redundant with FYN) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SRC term: id: UniProtKB:P12931 label: Proto-oncogene tyrosine-protein kinase Src function: preferred_term: non-membrane spanning protein tyrosine kinase activity term: id: GO:0004715 label: non-membrane spanning protein tyrosine kinase activity targets: - preferred_term: DAB1 term: id: UniProtKB:O75553 label: Disabled homolog 1 locations: - preferred_term: cytoplasmic side of plasma membrane term: id: GO:0009898 label: cytoplasmic side of plasma membrane role_description: >- Dispensable alone but needed when FYN is absent; FYN and SRC together account for almost all Reelin-induced DAB1 phosphorylation. evidence: - source_id: PMID:16162939 statement: Combined loss of Src and Fyn nearly abolishes Dab1 tyrosine phosphorylation and gives a dab1-like phenotype. supporting_text: although Src is dispensable and although the absence of Fyn causes an intermediate phenotype, the combined absence of Src and Fyn almost abolishes tyrosine phosphorylation of Dab1 and causes defects in the fetal cortex and cerebellum very similar to those of dab1 mutants of the same age. - order: 3 role: PI3K effector branch node: id: reelin_pi3k_branch label: Phospho-DAB1 recruitment of class IA PI3K via p85-alpha (PIK3R1) module_type: REGULATORY_STEP description: >- Reelin induces binding of DAB1 to the p85-alpha regulatory subunit of class IA PI3K; PI3K activation needs Src-family kinase activity and leads to AKT activation and GSK3B inhibition. PI3K signalling is needed for a normal cortical plate. annotons: - id: pik3r1_pi3k_regulator label: PIK3R1 (p85-alpha) PI3K regulator activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PIK3R1 term: id: UniProtKB:P27986 label: Phosphatidylinositol 3-kinase regulatory subunit alpha function: preferred_term: 1-phosphatidylinositol-3-kinase regulator activity term: id: GO:0046935 label: 1-phosphatidylinositol-3-kinase regulator activity locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Couples phospho-DAB1 to the p110 catalytic subunit and so to PIP3 production and AKT activation. evidence: - source_id: PMID:12882964 statement: PI3K activation by Reelin needs Src-family kinases and the Reelin-triggered Dab1-p85alpha interaction. supporting_text: PI3K activation by Reelin requires Src family kinase activity and depends on the Reelin-triggered interaction of Dab1 with the PI3K regulatory subunit p85alpha. - source_id: PMID:12882964 statement: PI3K signalling is required for Reelin-dependent cortical plate formation. supporting_text: PI3K signaling is required for the formation of a normal cortical plate, a step that is dependent upon Reelin signaling. - order: 4 role: AKT activation downstream of PI3K node: id: reelin_akt_activation label: AKT activation and GSK3B inhibition (by reference) description: >- Included by reference to the AKT activation step of the generic PI3K-AKT-mTOR module; Reelin-activated AKT inhibits GSK3B and lowers tau phosphorylation. This is the PI3K-Akt subpathway (PW:0000232) that RGD links from the diagram. module_ref: pi3k_akt_mtor#akt_activation evidence: - source_id: PMID:12882964 statement: Reelin signalling activates PI3K, AKT and inhibits GSK3B. supporting_text: This results in activation of phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt, and the inhibition of glycogen synthase kinase 3beta - order: 5 role: LIS1 effector branch node: id: reelin_lis1_branch label: Phospho-DAB1 binding to LIS1 (PAFAH1B1) module_type: REGULATORY_STEP description: >- LIS1 binds DAB1 in a Reelin-induced, phosphorylation-dependent manner, and reduced LIS1 dosage worsens the layering defects of Reelin-pathway mutants. LIS1 regulates cytoplasmic dynein and so links the signal to nucleokinesis in migrating neurons. annotons: - id: pafah1b1_lis1 label: LIS1 (PAFAH1B1) cytoskeletal motor regulator activity participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PAFAH1B1 term: id: UniProtKB:P43034 label: Platelet-activating factor acetylhydrolase IB subunit beta function: preferred_term: cytoskeletal motor regulator activity term: id: GO:0140659 label: cytoskeletal motor regulator activity processes: - preferred_term: neuron migration term: id: GO:0001764 label: neuron migration locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Binds phospho-DAB1; regulates dynein-driven nuclear translocation in migrating neurons. evidence: - source_id: PMID:14578885 statement: Dab1 and Lis1 bind in a Reelin-induced, phosphorylation-dependent way. supporting_text: Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. - source_id: PMID:14578885 statement: Compound Reln-pathway and Pafah1b1 heterozygous mutants have enhanced layering defects. supporting_text: Compound mutant mice with disruptions in the Reln pathway and heterozygous Pafah1b1 mutations had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. - order: 6 role: signal termination by phospho-DAB1 ubiquitination and degradation node: id: dab1_degradation label: CRL5(SOCS7) ubiquitination and proteasomal degradation of phospho-DAB1 module_type: REGULATORY_STEP description: >- Tyrosine-phosphorylated DAB1 is recognised by the SOCS-box adaptor SOCS7 and polyubiquitinated by the cullin-5 RING ligase (CUL5 scaffold, RNF7/RBX2 RING subunit, Elongin B/C adaptor), then degraded by the proteasome. Loss of CUL5, RNF7 or SOCS7 lets active DAB1 accumulate and neurons overshoot their target layer. concepts: - preferred_term: Cul5-RING ubiquitin ligase complex term: id: GO:0031466 label: Cul5-RING ubiquitin ligase complex - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence: - source_id: PMID:14645539 statement: Reelin makes Dab1 polyubiquitinated and degraded by the proteasome, and this requires Dab1 tyrosine phosphorylation. supporting_text: in response to Reelin it becomes polyubiquitinated and degraded via the proteasome pathway. We have established that tyrosine phosphorylation of Dab1 is required for its degradation. - source_id: PMID:17974915 statement: Cul5 ablation in migrating neurons causes accumulation of active Dab1 and excess migration. supporting_text: Ablation of Cul5 in migrating neurons causes an accumulation of active Dab1 protein and a unique cortical layering defect, characterized by excess migration and buildup of neurons at the top of the cortical plate. annotons: - id: socs7_substrate_adaptor label: SOCS7 substrate adaptor for phospho-DAB1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SOCS7 term: id: UniProtKB:O14512 label: Suppressor of cytokine signaling 7 function: preferred_term: ubiquitin-like ligase-substrate adaptor activity term: id: GO:1990756 label: ubiquitin-like ligase-substrate adaptor activity targets: - preferred_term: tyrosine-phosphorylated DAB1 term: id: UniProtKB:O75553 label: Disabled homolog 1 processes: - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Neocortical CRL5 substrate adaptor; upregulated during projection-neuron migration. The cerebellum uses other CRL5 adaptors. evidence: - source_id: PMID:24210661 statement: SOCS7 is required for neocortical layering and SOCS7-CRL5 complexes drive Dab1 ubiquitylation and turnover. supporting_text: SOCS7, a CRL5 substrate adaptor protein, is also required for neocortical layering. SOCS7-CRL5 complexes stimulate the ubiquitylation and turnover of Dab1. - source_id: PMID:17974915 statement: SOCS proteins in Cul5 complexes bind phospho-Dab1. supporting_text: Cul5 forms complexes with SOCS (suppressors of cytokine signaling) proteins, which bind to phosphorylated Dab1 and target it for degradation in tissue culture cells. gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002746 title: SOCS7 ubiquitin-like ligase-substrate adaptor activity (GO:1990756) with input DAB1 - id: cul5_scaffold label: CUL5 ubiquitin ligase complex scaffold participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CUL5 term: id: UniProtKB:Q93034 label: Cullin-5 function: preferred_term: ubiquitin ligase complex scaffold activity term: id: GO:0160072 label: ubiquitin ligase complex scaffold activity processes: - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Cullin scaffold that holds SOCS7-Elongin B/C and RNF7 together. evidence: - source_id: PMID:17974915 statement: Dab1 degradation depends on Cul5. supporting_text: degradation of Dab1 depends on Dab1 phosphorylation at specific tyrosine residues and on the E3 ubiquitin ligase component Cullin 5 (Cul5) gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002770 title: CUL5 ubiquitin ligase complex scaffold activity (GO:0160072) - id: rnf7_ring_ligase label: RNF7 (RBX2) RING ubiquitin ligase activity on DAB1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RNF7 term: id: UniProtKB:Q9UBF6 label: RING-box protein 2 function: preferred_term: ubiquitin protein ligase activity term: id: GO:0061630 label: ubiquitin protein ligase activity targets: - preferred_term: tyrosine-phosphorylated DAB1 term: id: UniProtKB:O75553 label: Disabled homolog 1 processes: - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- RING subunit specific to CRL5; Rbx2 loss causes Dab1-dependent neocortical and cerebellar ectopias. evidence: - source_id: PMID:24210661 statement: Rbx2 mutation causes Dab1-dependent ectopias. supporting_text: Rbx2 mutation causes neocortical and cerebellar ectopias dependent on Dab1, a key signaling protein in the Reelin pathway. gocam_associations: - model: gomodel:66187e4700002704 activity: gomodel:66187e4700002704/66187e4700002756 title: RNF7 ubiquitin protein ligase activity (GO:0061630), directly negatively regulates DAB1 connections: - source: reelin_receptor_binding target: dab1_phosphorylation connection_type: POSITIVELY_REGULATES description: >- Receptor clustering brings receptor-bound DAB1 together and triggers its Src-family kinase phosphorylation (RELN -> LRP8 -> FYN -> DAB1 in both GO-CAMs). - source: dab1_phosphorylation target: reelin_pi3k_branch connection_type: POSITIVELY_REGULATES description: Phospho-DAB1 recruits p85-alpha and activates PI3K. - source: reelin_pi3k_branch target: reelin_akt_activation connection_type: POSITIVELY_REGULATES description: PI3K-generated PIP3 drives AKT activation, which inhibits GSK3B. - source: dab1_phosphorylation target: reelin_lis1_branch connection_type: POSITIVELY_REGULATES description: Phospho-DAB1 binds LIS1. - source: dab1_phosphorylation target: dab1_degradation connection_type: PROVIDES_INPUT_FOR description: >- Tyrosine-phosphorylated DAB1 is the substrate recognised by SOCS7 (FYN directly provides input for SOCS7 in gomodel:66187e4700002704). - source: dab1_degradation target: dab1_phosphorylation connection_type: NEGATIVELY_REGULATES description: >- Ubiquitination and degradation of phospho-DAB1 terminate the signal (RNF7 directly negatively regulates DAB1 activity in the GO-CAM), the pathway's negative feedback. knowledge_gaps: - gap_statement: >- How Reelin signalling through ApoER2, DAB1 and Src-family kinases changes NMDA and AMPA receptor function in the adult brain is incompletely understood: which tyrosines on GRIN2A/GRIN2B are phosphorylated and by which kinase, whether DAB1 binds the receptor complex directly, and how much of the reported enhancement of long-term potentiation goes through NMDA receptor phosphorylation versus PI3K-dependent AMPA receptor insertion. gap_kind: - BIOLOGY - gap_statement: >- Whether alpha3beta1 integrin and cadherin-related neuronal receptors act as Reelin co-receptors that contribute to DAB1 signalling in vivo, or only modulate adhesion in parallel, is unresolved; the reported binding has not been reconciled with the reeler-like phenotype of the VLDLR/ApoER2 double knockout. gap_kind: - BIOLOGY