Reelin signaling pathway (Homo sapiens)

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Bibliography

1. 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
2. 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
3. Gao Z, Godbout R.; ''Reelin-Disabled-1 signaling in neuronal migration: splicing takes the stage.''; PubMed Europe PMC Scholia
4. 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
5. 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
6. Stranahan AM, Erion JR, Wosiski-Kuhn M.; ''Reelin signaling in development, maintenance, and plasticity of neural networks.''; PubMed Europe PMC Scholia
7. 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
8. 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
9. Folsom TD, Fatemi SH.; ''The involvement of Reelin in neurodevelopmental disorders.''; PubMed Europe PMC Scholia
10. Ohshima T, Suzuki H, Morimura T, Ogawa M, Mikoshiba K.; ''Modulation of Reelin signaling by Cyclin-dependent kinase 5.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:456216 (ChEBI)
ATP	Metabolite	CHEBI:30616 (ChEBI)
DAB1	Protein	O75553 (Uniprot-TrEMBL)
DAB1	Protein	O75553 (Uniprot-TrEMBL)
FYN	Protein	P06241 (Uniprot-TrEMBL)
RELN	Protein	P78509 (Uniprot-TrEMBL)
RELN:VLDLR:DAB1:SH3KBP1	Complex	R-HSA-8855258 (Reactome)
RELN:VLDLR:DAB1	Complex	R-HSA-8855235 (Reactome)
RELN:VLDLR:p-Y198,220,232-DAB1:SH3KBP1	Complex	R-HSA-8855226 (Reactome)
RELN:VLDLR	Complex	R-HSA-8854471 (Reactome)
RELN	Protein	P78509 (Uniprot-TrEMBL)
SH3KBP1	Protein	Q96B97 (Uniprot-TrEMBL)
SH3KBP1	Protein	Q96B97 (Uniprot-TrEMBL)
VLDLR	Protein	P98155 (Uniprot-TrEMBL)
VLDLR	Protein	P98155 (Uniprot-TrEMBL)
p-Y198,220,232-DAB1	Protein	O75553 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-8855237 (Reactome)
ATP			R-HSA-8855237 (Reactome)
DAB1			R-HSA-8855232 (Reactome)
FYN		mim-catalysis	R-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:SH3KBP1	Arrow	R-HSA-8855259 (Reactome)
RELN:VLDLR:DAB1:SH3KBP1			R-HSA-8855237 (Reactome)
	RELN:VLDLR:DAB1	Arrow	R-HSA-8855232 (Reactome)
RELN:VLDLR:DAB1			R-HSA-8855259 (Reactome)
	RELN:VLDLR:p-Y198,220,232-DAB1:SH3KBP1	Arrow	R-HSA-8855237 (Reactome)
	RELN:VLDLR	Arrow	R-HSA-8854466 (Reactome)
RELN:VLDLR			R-HSA-8855232 (Reactome)
RELN			R-HSA-8854466 (Reactome)
SH3KBP1			R-HSA-8855259 (Reactome)
VLDLR			R-HSA-8854466 (Reactome)