Disabled 1 (Dab1) is an 80 kDa protein that is encoded by the Disabled-1 gene locus which is mutated in scrambler and yotari mutant mice. Phenotypically, the mutation of this gene produces motor defects and ataxia, disruption of neuronal migration, and severe cerebellar hypoplasia. Dab1 is an intracellular adapter protein that functions in downstream signaling events initiated by the secreted protein reelin. Dab1 contains a phosphotyrosine binding (PTB) domain in the amino terminus. Tyrosine phosphorylation of Dab1 is increased by reelin binding to the Very Low Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2) through stimulation of Src family kinases. Src family kinase and c-Abl activities are themselves then stimulated by binding to tyrosine phosphorylated Dab1. Dab1 also mediates activation of Akt (PKB) by reelin resulting in inhibition of glycogen synthase kinase 3 beta (GSK-3 beta) and decreased phosphorylation of the microtubule-associated protein, Tau. Dab1 serine 491 is phosphorylated in a Cdk5-dependent manner and regulates, likely indirectly, Reelin-induced signaling during neural cortex development.
