Cullin 5 regulates Dab1 protein levels and neuron positioning during cortical development

Abstract

[Keywords: Cullin; Dab1; Reelin; cortical development; neuronal migration; ubiquitin] Supplemental material is available at http://www.genesdev.org.

A missed exit: Reelin sets in motion Dab1 polyubiquitination to put the break on neuronal migration: Figure 1.

“…Moreover, inhibition of Dab1 tyrosine phosphorylation and inhibition of SFK activation blocks Dab1 down-regulation (Arnaud et al 2003b;Bock et al 2004;Kuo et al 2005). Feng et al (2007) identified two critical Dab1 tyrosine phosphorylation sites (primary Tyr198, and also Tyr185), both at YQxI sequences, essential for the Dab1 degradation in response to Reelin, in an embryonic cortical neuron culture system. Tyr198 had been formerly predicted as a potential Reelin-induced Dab1 phosphorylation site by a Web-based PESTfind algorithm; however, the same method failed to identify Tyr185, but instead predicted the importance of Tyr220 .…”

“…Cold Spring Harbor Laboratory Press on April 3, 2019 -Published by genesdev.cshlp.org Downloaded from Feng et al (2007) identifed another type of EBC potentially regulating Dab1 in vivo. They also used nonneuronal cells lines such as COS7, in which Dab1, when coexpressed with Fyn and Src, is known to be constitutively tyrosine phophorylated but not degraded.…”

“…This suggests that a component of the degradation machinery targeting phospho-tyrosine Dab1 is absent or limiting in this in vitro system, which thus makes it particularly adapted for a candidate approach. Feng et al (2007) tested several E3 ubiquitin ligases in this nonneuronal cell system and show that the SOCS1-3 ligases can bind to Dab1, and induce Tyr185 or Tyr198 phophorylated Dab1 degradation, in a Fyn-dependent manner. Interestingly, they also tested Cbl in this assay and show that it fails to induce Dab1 degradation, further invalidating the Cbl implication hypothesis.…”

“…Interestingly, they also tested Cbl in this assay and show that it fails to induce Dab1 degradation, further invalidating the Cbl implication hypothesis. Because many SOCS proteins are expressed during brain development (among them SOCS1-3) and might be functionally redundant, Feng et al (2007) chose to study the consequence of the inactivation of another component of the SOCS-containing EBC on Reelin-induced degradation of Dab1: the cullin Cul5 (Petroski and Deshaies 2005). Cul5 recently has been shown and confirmed in the study by Feng et al (2007) to be expressed in mouse cortical neurons (Lein et al 2007), but its role was so far completely unknown.…”

“…The observations that mutations of Dab1 phenocopy the Rln mutation, and that Dab1 is up-regulated in reeler mice suggested the existence of a negative feedback loop in Reelin signaling via the regulation of Dab1 levels. In the previous issue of Genes & Development, Feng et al (2007) presented the first coherent model to explain the mechanism of Reelin-mediated Dab1 downregulation. They proposed that Reelin both activates and down-regulates its effector Dab1, first by inducing its phosphorylation, which then causes its targeting by an E3 ubiquitin ligase complex (EBC) containing SOCS family proteins and Cullin5 (Cul5).…”