id: PW:0000388 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000388 title: reelin signaling pathway description: The Reelin signaling pathway controls neuronal migration and positioning in central nervous system (CNS) development, as well as synaptic plasticity and memory, operating through different receptors, probably depending on context. Defects in the Reelin gene lead to the reeler phenotype in mice, exhibiting neural positioning defects, and to lissencephaly in humans, with malformation of the cerebrum and cerebellum. Reelin signaling is also thought to be involved in Alzheimer's disease, autism andother neurological disorders. Reelin expression is regulated epigenetically, and transcriptionally by thyroid hormone and, along with NMDA (N-methyl-D-aspartate) receptor subunits, by nuclear proteins CASK, CINAP and Tbr-1. The two best-studied receptors for Reelin are the apolipoprotein E receptor 2 (ApoER2; Lrp8) and the very low density lipoprotein receptor (VLDLR). Competing ligands for these receptors, such as ApoE and RAP, can interfere with Reeling signaling. The secreted glycoprotein Reelin is processed, probably by metalloproteases, into fragments less effective at signaling. Acting as an oligomer, full-length Reelin more effectively binds to the high-affinity receptors ApoER2 and VLDLR, causing clustering. This causes the membrane- and receptor-associated cytosolic Disabled-1 (Dab1) adapter protein to be tyrosine-phosphorylated by src-family kinases such as Fyn. Reelin-induced phosphorylated Dab1 (Dab1-P) stimulates further Src kinase activation, as well as a phosphatidylinositol 3-kinase (PI3K) pathway that activates protein kinase B (Akt) and inhibits glycogen synthase kinase-3beta,which is involved in modulating antiapoptotic, neuroprotective pathways of cell growth and survival. Stimulation of the PI3K pathway also results in reduced phosphorylation of Tau protein, involved in microtubule organization. Dab1-P can alternatively signal through Lis1 (Pafah1b1) and the alpha subunits of the Pafah1b complex to control CNS layer formation. Fine tuning of Reelin signaling may occur via phosphorylation-dependent ubiquitination of Dab1-P, thought to be associated with endocytosis of the reeling signaling complex and receptor recycling. There is evidence that alpha3beta1 integrins (Itga3, Itgb1) are also involved alongside ApoER2s and VLDLRs in transmitting Reelin signals to control neuronal positioning. Cadherin-related neuronal receptors bind Reelin and Src kinases as well, and serve as functional Reelin receptors. In adults, Reelin is thought to mediate synaptic plasticity , memory and learning through Dab1-P, via src kinases and NMDA receptors (e. g. Grin2a, Grin2b), or via PI3K and tetrameric AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors (e. g. Gria1). To access the ontology report for annotations, GViewer and downloads, click here diagram_image: https://rgd.mcw.edu/pathway/PW0000388/Reelin%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000388/Reelin%20signaling%20pathway/Reelin%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000232 label: phosphatidylinositol 3-kinase-Akt signaling pathway - id: PW:0000286 label: integrin mediated signaling pathway diagram_gene_links: - id: RGD:628770 label: Dab1 - id: RGD:2641 label: Fyn - id: RGD:621531 label: Gria1 - id: RGD:2737 label: Grin2a - id: RGD:2738 label: Grin2b - id: RGD:1310333 label: Itga3 - id: RGD:2927 label: Itgb1 - id: RGD:1305729 label: Lrp8 - id: RGD:620331 label: PAFAH1B1 - id: RGD:620332 label: Pafah1b2 - id: RGD:620333 label: PAFAH1B3 - id: RGD:3329 label: Pik3r1 - id: RGD:3553 label: Reln - id: RGD:3963 label: Vldlr diagram_chemicals: - id: PUBCHEM.COMPOUND:5460341 label: Ca2+ - id: PUBCHEM.COMPOUND:5497157 label: PtdIns4P diagram_edges: - source: Ca2+ relation: positively_affects target: Gria1 - source: Ca2+ relation: positively_affects target: learning and/or memory - source: Dab1 relation: associated_with target: Gria1 - source: Dab1 relation: associated_with target: Lrp8 - source: Dab1 relation: associated_with target: PAFAH1B1 - source: Dab1 relation: associated_with target: PtdIns4P - source: Dab1 relation: associated_with target: Vldlr - source: Grin2a relation: associated_with target: Lrp8 - source: Grin2a relation: associated_with target: Vldlr - source: Grin2b relation: associated_with target: Lrp8 - source: Grin2b relation: associated_with target: Vldlr - source: Itga3 relation: associated_with target: Reln - source: Itga3 relation: positively_affects target: integrin mediated signaling pathway - source: Itgb1 relation: associated_with target: Reln - source: Itgb1 relation: positively_affects target: integrin mediated signaling pathway - source: Lrp8 relation: associated_with target: Reln - source: PAFAH1B1 relation: positively_affects target: brain development - source: PAFAH1B1 relation: positively_affects target: neuronal migration - source: PAFAH1B3 relation: associated_with target: Vldlr - source: Pafah1b2 relation: associated_with target: Vldlr - source: Pik3r1 relation: positively_affects target: phosphatidylinositol 3-kinase-Akt signaling pathway - source: Reln relation: associated_with target: Vldlr diagram_labels: - brain development - Dab1 --+> Fyn - Dab1 --+> Src-related kinases - Fyn --+> Dab1 - Gria1 --+> synaptic transmission - Grin2a --+> Ca2+ - Grin2b --+> Ca2+ - Itga3 --+> Dab1 - Itgb1 --+> Dab1 - learning and/or memory - neuronal migration - P-tyrosine - Src-related kinases --+> Dab1 - Src-related kinases --+> Grin2a - Src-related kinases --+> Grin2b - synaptic transmission - thyroid hormones - thyroid hormones --+> Reln diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/src-related-kinases label: Src-related kinases references: - id: RGD:2317930 citation: Beffert U, etal., Neuron. 2005 Aug 18;47(4):567-79. - id: RGD:2317973 citation: Fatemi SH, etal., Biol Psychiatry. 2005 Apr 1;57(7):777-87. - id: RGD:2324970 citation: Tissir F and Goffinet AM, Nat Rev Neurosci. 2003 Jun;4(6):496-505. - id: RGD:2324974 citation: Myant NB Proc Biol Sci. 2010 Feb 7;277(1680):345-51. Epub 2009 Oct 21. - id: RGD:2325284 citation: Levenson JM, etal., Biochim Biophys Acta. 2008 Aug;1779(8):422-31. Epub 2008 Jan 12. - id: RGD:2325851 citation: Fatemi SH Mol Psychiatry. 2005 Mar;10(3):251-7. - id: RGD:4107040 citation: Zhang G, etal., PLoS One. 2007 Feb 28;2(2):e252. - id: RGD:4108507 citation: Qiu S, etal., J Neurosci. 2006 Dec 13;26(50):12943-55. - id: RGD:5129717 citation: Senzaki K, etal., Cell. 1999 Dec 10;99(6):635-47. - id: RGD:5129762 citation: Arnaud L, etal., Curr Biol. 2003 Jan 8;13(1):9-17. - id: RGD:5129763 citation: Bock HH and Herz J, Curr Biol. 2003 Jan 8;13(1):18-26. - id: RGD:5129822 citation: D'Arcangelo G Neuron. 2005 Aug 18;47(4):471-3. - id: RGD:5129891 citation: Herz J and Chen Y, Nat Rev Neurosci. 2006 Nov;7(11):850-9. - id: RGD:5129953 citation: Kerjan G and Gleeson JG, Genes Dev. 2007 Nov 15;21(22):2850-4.