The main<unk>  signaling cascade (ApoER2 and VLDLR) and its interaction with LIS1. Zhang et al., 2008 SFK: Src family kinases.JIP: JNK-interacting protein 1 Receptors<unk> 's control of cell-cell interactions is thought to be mediated by binding of<unk>  to the two members of low density lipoprotein receptor gene family: VLDLR and the ApoER2. The two main<unk>  receptors seem to have slightly different roles: VLDLR conducts the stop signal, while ApoER2 is essential for the migration of late-born neocortical neurons. It also has been shown that the N-terminal region of<unk> , a site distinct from the region of<unk>  shown to associate with VLDLR/ApoER2 binds to the alpha-3-beta-1 integrin receptor. The proposal that the protocadherin CNR1 behaves as a<unk>  receptor has been disproven. As members of lipoprotein receptor superfamily, both VLDLR and ApoER2 have in their structure an internalization domain called NPxY motif. After binding to the receptors<unk>  is internalized by endocytosis, and the N-terminal fragment of the protein is re-secreted. This fragment may serve postnatally to prevent apical dendrites of cortical layer II/III pyramidal neurons from overgrowth, acting via a pathway independent of canonical<unk>  receptors.<unk>  receptors are present on both neurons and glial cells. Furthermore, radial glia express the same amount of ApoER2 but being ten times less rich in VLDLR. beta-1 integrin receptors on glial cells play more important role in neuronal layering than the same receptors on the migrating neuroblasts.<unk> -dependent strengthening of long-term potentiation is caused by ApoER2 interaction with NMDA receptor. This interaction happens when ApoER2 has a region coded by exon 19. ApoER2 gene is alternatively spliced, with the exon 19-containing variant more actively produced during periods of activity. According to one study, the hippocampal<unk>  expression rapidly goes up when there is need to store a memory, as demethylases open up the RELN gene. The activation of dendrite growth by<unk>  is apparently conducted through Src family kinases and is dependent upon the expression of Crk family proteins, consistent with the interaction of Crk and CrkL with tyrosine-phosphorylated Dab1. Moreover, a Cre-loxP recombination mouse model that lacks Crk and CrkL in most neurons was reported to have the reeler phenotype, indicating that Crk/CrkL lie between DAB1 and Akt in the<unk>  signaling chain. Signaling cascades<unk>  activates the signaling cascade of Notch-1, inducing the expression of FABP7 and prompting progenitor cells to assume radial glial phenotype. In addition, corticogenesis in vivo is highly dependent upon<unk>  being processed by embryonic neurons, which are thought to secrete some as yet unidentified metalloproteinases that free the central signal-competent part of the protein. Some other unknown proteolytic mechanisms may also play a role. It is supposed that full-sized<unk>  sticks to the extracellular matrix fibers on the higher levels, and the central fragments, as they are being freed up by the breaking up of<unk> , are able to permeate into the lower levels. It is possible that as neuroblasts reach the higher levels they stop their migration either because of the heightened combined expression of all forms of<unk> , or due to the peculiar mode of action of the full-sized<unk>  molecules and its homodimers. The intracellular adaptor DAB1 binds to the VLDLR and ApoER2 through an NPxY motif and is involved in transmission of<unk>  signals through these lipoprotein receptors. It becomes phosphorylated by Src and Fyn kinases and apparently stimulates the actin cytoskeleton to change its shape, affecting the proportion of integrin receptors on the cell surface, which leads to the change in adhesion. Phosphorylation of DAB1 leads to its ubiquitination and subsequent degradation, and this explains the heightened levels of DAB1 in the absence of<unk> . Such negative feedback is thought to be important for proper cortical lamination. Activated by two antibodies, VLDLR and ApoER2 cause DAB1 phosphorylation but seemingly without the subsequent degradation and without rescuing the reeler phenotype, and this may indicate that a part of the signal is conducted independently of DAB1. BLBP by affecting the NOTCH1 cascade. A fragment of an illustration from Keilani et al., 2008. A protein having an important role in lissencephaly and accordingly called LIS1 (PAFAH1B1), was shown to interact with the intracellular segment of VLDLR, thus reacting to the activation of<unk>  pathway. Complexes<unk>  molecules have been shown to form a large protein complex, a disulfide-linked homodimer. If the homodimer fails to form, efficient tyrosine phosphorylation of DAB1 in vitro fails. Moreover, the two main receptors of<unk>  are able to form clusters that most probably play a major role in the signaling, causing the intracellular adaptor DAB1 to dimerize or oligomerize in its turn. Such clustering has been shown in the study to activate the signaling chain even in the absence of<unk>  itself. In addition,<unk>  itself can cut the peptide bonds holding other proteins together, being a serine protease, and this may affect the cellular adhesion and migration processes.<unk>  signaling leads to phosphorylation of actin-interacting protein cofilin 1 at ser3; this may stabilize the actin cytoskeleton and anchor the leading processes of migrating neuroblasts, preventing their further growth. Interaction with Cdk5 Cyclin-dependent kinase 5 (Cdk5), a major regulator of neuronal migration and positioning, is known to phosphorylate DAB1 and other cytosolic targets of<unk>  signaling, such as Tau, which could be activated also via<unk> -induced deactivation of GSK3B, and NUDEL, associated with Lis1, one of the DAB1 targets. LTP induction by<unk>  in hippocampal slices fails in p35 knockouts. P35 is a key Cdk5 activator, and double p35/Dab1, p35/RELN, p35/ApoER2, p35/VLDLR knockouts display increased neuronal migration deficits, indicating a synergistic action of<unk>  → ApoER2/VLDLR → DAB1 and p35/p39 → Cdk5 pathways in the normal corticogenesis.
Reelin
Embelin
Equilin
AmnesiA
Telokin
Basigin
Peripherin
Collectin