Reelin Signaling in Neurons

Reelin is a large extracellular glycoprotein involved in the development of architectonic patterns, synthesized primarily in Cajal-Retzius cells of the human embryonic marginal zone. In the hippocampus, reelin also regulates the growth and/or distribution of afferent entorhinal and commissural axons.At the surface of target cells, reelin binds to two lipoprotein receptors, VLDLR and ApoER2, which relay the signal into the cell via the adapter protein Dab1. ApoE also binds to ApoER2, and while not a competitive inhibitor to reelin, can (especially the ApoE4 allele) induce long-term receptor internalization. Dab1 associates with an NPXY motif in the cytoplasmic region of VLDLR and ApoER2. Reelin binds to these receptors, triggering tyrosine phosphorylation of Dab1, which promotes an interaction with several nonreceptor tyrosine kinases, including Src, Fyn, and Abl through their SH2 domains. In the absence of reelin or the receptors, Dab1 accumulates in a hypo-phosphorylated form. Tyrosine phosphorylated Dab1 may couple reelin signaling to downstream molecular machinery involved in cell positioning. The PTB domain of Dab1 also binds to the transmembrane glycoproteins of amyloid precursor protein (APP) and low-density lipoprotein receptor families and the phosphatase SHIP. The function of Dab1 binding to LDL receptor-related protein (LRP)-α-2 macroglobulin receptor, APP, and their relatives could potentially regulate trafficking or processing. Dab1 also interact with Lis1. Lis1 functionally interacts with the α subunits of the PAFAH1B complex, PAFAH1B2 (α2) and PAFAH1B3 (α1). Lis1 also interacts with NudEL/cytoplasmic dynein complex, NudC19 and mNude23 to regulate lamination in the CNS.CDK5 can also influence reelin signaling through phosphorylation of Dab1.CDK5, in conjunction with another cytoplasmic serine/threonine kinase, GSK3-β and PP2A, regulates the phosphorylation state of the microtubule-associated protein Tau. Phosphorylation of Tau affects its affinity for microtubules and its ability to form paired helical filaments from which the neurofibrillary tangles in Alzheimer's disease develop. CDK5 is also known to interact with other known pathways regulating neuronal migration such as Lis1/NudEL. In addition to its role in neuronal migration, CDK5 is also implicated in neurodegeneration through dysregulation of its kinase activity. Dysregulation is attributed to the calpain-mediated cleavage of p35 to a C-terminal truncated fragment known as p25. p25 causes mislocalization and prolonged activation of CDK5. CDK5 also phosphorylates APP, which in turn contributes to the pathogenesis of Alzheimer's disease. ApoER2 associates with the JNK family of interacting proteins, JIP1 and JIP2. JIP are kinase-scaffolding proteins important in the JNK kinase signaling pathway, and JIP1 associates with RhoGEF. Thus, activation of MLK3, MKK7, and JNK, which assemble on JIPs, is a downstream consequence of reelin signaling. α3/β1 integrin and protocadherins of the cadherin-related neuronal receptors (CNR) family may also modulate reelin signaling. (Upgraded 09/2019)