Reelin signalling pathway (Homo sapiens)

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2, 58-103, 4, 6, 71, 37cytosolVLDLRRELN:VLDLR:p-Y198,220,232-DAB1:SH3KBP1RELN:VLDLR:DAB1RELNRELN:VLDLR:DAB1:SH3KBP1SH3KBP1RELN SH3KBP1 RELN DAB1VLDLR VLDLR ATPDAB1 SH3KBP1 VLDLR VLDLR FYNDAB1 RELN RELN RELN:VLDLRp-Y198,220,232-DAB1 ADP


Description

Reelin (RELN) is an extracellular, multifunctional signal glycoprotein that controls not only the positioning of neurons in the developing brain, but also their growth, maturation, and synaptic activity in the adult brain (Stranahan et al. 2013). Abnormal Reelin expression in the brain is implicated in a number of neuropsychiatric disorders including autism, schizophrenia, bipolar disorder and Alzheimer's disease (Folsom & Fatemi 2013). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8866376
Reactome-version 
Reactome version: 73
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Fuchigami T, Sato Y, Tomita Y, Takano T, Miyauchi SY, Tsuchiya Y, Saito T, Kubo K, Nakajima K, Fukuda M, Hattori M, Hisanaga S.; ''Dab1-mediated colocalization of multi-adaptor protein CIN85 with Reelin receptors, ApoER2 and VLDLR, in neurons.''; PubMed Europe PMC Scholia
  2. DeSilva U, D'Arcangelo G, Braden VV, Chen J, Miao GG, Curran T, Green ED.; ''The human reelin gene: isolation, sequencing, and mapping on chromosome 7.''; PubMed Europe PMC Scholia
  3. Impagnatiello F, Guidotti AR, Pesold C, Dwivedi Y, Caruncho H, Pisu MG, Uzunov DP, Smalheiser NR, Davis JM, Pandey GN, Pappas GD, Tueting P, Sharma RP, Costa E.; ''A decrease of reelin expression as a putative vulnerability factor in schizophrenia.''; PubMed Europe PMC Scholia
  4. Bar I, Tissir F, Lambert de Rouvroit C, De Backer O, Goffinet AM.; ''The gene encoding disabled-1 (DAB1), the intracellular adaptor of the Reelin pathway, reveals unusual complexity in human and mouse.''; PubMed Europe PMC Scholia
  5. Katyal S, Gao Z, Monckton E, Glubrecht D, Godbout R.; ''Hierarchical disabled-1 tyrosine phosphorylation in Src family kinase activation and neurite formation.''; PubMed Europe PMC Scholia
  6. Gao Z, Godbout R.; ''Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage.''; PubMed Europe PMC Scholia
  7. Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, Herz J.; ''Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation.''; PubMed Europe PMC Scholia
  8. Ohshima T, Suzuki H, Morimura T, Ogawa M, Mikoshiba K.; ''Modulation of Reelin signaling by Cyclin-dependent kinase 5.''; PubMed Europe PMC Scholia
  9. Stranahan AM, Erion JR, Wosiski-Kuhn M.; ''Reelin signaling in development, maintenance, and plasticity of neural networks.''; PubMed Europe PMC Scholia
  10. Folsom TD, Fatemi SH.; ''The involvement of Reelin in neurodevelopmental disorders.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
113117view11:18, 2 November 2020ReactomeTeamReactome version 74
112351view15:27, 9 October 2020ReactomeTeamReactome version 73
101252view11:14, 1 November 2018ReactomeTeamreactome version 66
100791view20:42, 31 October 2018ReactomeTeamreactome version 65
100333view19:19, 31 October 2018ReactomeTeamreactome version 64
99878view16:02, 31 October 2018ReactomeTeamreactome version 63
99435view14:37, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99110view12:39, 31 October 2018ReactomeTeamreactome version 62
93462view11:24, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
DAB1 ProteinO75553 (Uniprot-TrEMBL)
DAB1ProteinO75553 (Uniprot-TrEMBL)
FYNProteinP06241 (Uniprot-TrEMBL)
RELN ProteinP78509 (Uniprot-TrEMBL)
RELN:VLDLR:DAB1:SH3KBP1ComplexR-HSA-8855258 (Reactome)
RELN:VLDLR:DAB1ComplexR-HSA-8855235 (Reactome)
RELN:VLDLR:p-Y198,220,232-DAB1:SH3KBP1ComplexR-HSA-8855226 (Reactome)
RELN:VLDLRComplexR-HSA-8854471 (Reactome)
RELNProteinP78509 (Uniprot-TrEMBL)
SH3KBP1 ProteinQ96B97 (Uniprot-TrEMBL)
SH3KBP1ProteinQ96B97 (Uniprot-TrEMBL)
VLDLR ProteinP98155 (Uniprot-TrEMBL)
VLDLRProteinP98155 (Uniprot-TrEMBL)
p-Y198,220,232-DAB1 ProteinO75553 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-8855237 (Reactome)
ATPR-HSA-8855237 (Reactome)
DAB1R-HSA-8855232 (Reactome)
FYNmim-catalysisR-HSA-8855237 (Reactome)
R-HSA-8854466 (Reactome) Reelin (RELN) (DeSilva et al. 1997) is an extracellular matrix serine protease highly expressed in the brain that plays a role in neural cell positioning during brain development by regulating their microtubule function and neuronal migration. It can bind to the extracellular domains of lipoprotein receptors VLDLR and APOER2 to induce tyrosine phosphorylation of disabled-1 (DAB1), an adaptor protein bound to the cytoplasmic tails of these receptors that is a phosphorylation target for a signaling cascade trigggered by RELN. This suggests VLDLR and APOER2 participate in transmitting the extracellular RELN signal to intracellular signaling processes initiated by DAB1 (Hiesberger et al. 1999). In post-mortem studies of schizophrenia sufferers, RELN was found to be significantly reduced (by up to 50%) in brain samples whereas DAB1 was observed to be at normal levels, suggesting a role for RELN in schizophrenia (Impagnatiello et al. 1998).
R-HSA-8855232 (Reactome) Reelin (RELN) is an extracellular matrix serine protease highly expressed in the brain that plays a role in neural cell positioning during brain development by regulating their microtubule function and neuronal migration. It can bind to the extracellular domains of lipoprotein receptors VLDLR and APOER2 to induce tyrosine phosphorylation of disabled-1 (DAB1), an adaptor protein bound to the cytoplasmic tails of these receptors that is a phosphorylation target for a signaling cascade trigggered by RELN (Bar et al. 2003, for a review see Gao & Godbout 2013).
R-HSA-8855237 (Reactome) One of the three domains in disabled homolog 1 (DAB1) is a tyrosine-rich region consists of five highly conserved tyrosine residues; Y185, Y198, Y200, Y220 and Y232. These residues correspond to two consensus Src family kinase recognition sites (YQxI, Y185 and Y198) and two consensus Abl/Crk recognition sites (YxVP, Y220 and Y232). At least three of the tyrosine residues (Y198, Y220 and Y232) can be phosphorylated by the Src kinase family member, tyrosine protein kinase fyn (FYN) in response to Reelin (RELN) stimulation (Katyal et al. 2007). Tyrosine-phosphorylated DAB1 acts as a hub to recruit different Src homology 2 (SH2) domain-containing proteins, including the p85 regulatory subunit of phosphatidylinositide-3-kinase (PI3K), cellular adaptors CrkL, Crk, Nck-beta and SOCS (suppressor of cytokine signaling) (Gao & Godbout 2013). Tyrosine phosphorylation of DAB1 also appears to strengthen the association of DAB1 with SH3KBP1 (aka CIN85), an adaptor protein involved in endocytic down-regulation of receptor-tyrosine kinases (Fuchigami et al. 2013).
R-HSA-8855259 (Reactome) SH3 domain-containing kinase-binding protein 1 (SH3KBP1, aka CIN85) is an adapter protein involved in the regulation of endocytosis and lysosomal degradation of ligand-induced receptor tyrosine kinases (Fuchigami et al. 2013).
RELN:VLDLR:DAB1:SH3KBP1ArrowR-HSA-8855259 (Reactome)
RELN:VLDLR:DAB1:SH3KBP1R-HSA-8855237 (Reactome)
RELN:VLDLR:DAB1ArrowR-HSA-8855232 (Reactome)
RELN:VLDLR:DAB1R-HSA-8855259 (Reactome)
RELN:VLDLR:p-Y198,220,232-DAB1:SH3KBP1ArrowR-HSA-8855237 (Reactome)
RELN:VLDLRArrowR-HSA-8854466 (Reactome)
RELN:VLDLRR-HSA-8855232 (Reactome)
RELNR-HSA-8854466 (Reactome)
SH3KBP1R-HSA-8855259 (Reactome)
VLDLRR-HSA-8854466 (Reactome)
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