Nck beta interacts with tyrosine-phosphorylated Disabled 1 and redistributes in reelin-stimulated neurons

Abstract

The tyrosine phosphorylation sites of the Disabled I (Dab1) docking protein are essential for the transmission of the Reelin signal, which regulates neuronal placement. Here we identify Nckbeta as a phosphorylation-dependent, Dab1-interacting protein. The SH2 domain of Nckbeta but not Nckalpha binds Dab1 phosphorylated on the Reelin-regulated site, Y220, or on Y232. Nckbeta is coexpressed with Dahl in the developing brain and in cultured neurons, where Reelin stimulation leads to the redistribution of Nckbeta from the cell soma into neuronal processes. We found that tyrosine-phosphorylated Dah1 in synergy with Nckbeta disrupts the actin cytoskeleton in transfected cells. In Drosophila melanogaster, exogenous expression of mouse Dahl causes tyrosine phosphorylation site-dependent morphological changes in the compound eye. This phenotype is enhanced by overexpression of the Drosophila Nck protein Dock, suggesting a conserved interaction between the Disabled and Nck family members. We suggest a model in which Dab1 phosphorylation leads to the recruitment of Nckbeta to the membrane, where it acts to remodel the actin cytoskeleton.