Splice-mediated motif switching regulates disabled-1 phosphorylation and SH2 domain interactions.

Disabled-1 ( Dab1) plays a key role in reelin-mediated neuronal migrationduring brain development. Tyrosine phosphorylationof Dab1at two YQXI and two YXVP motifs recruits multiple SH2 domains, resulting in activation of a wide range of signaling cascades. However, the molecular mechanisms underlying the coordinated regulation of Dab1downstream effectors remain poorly understood. Here, we show that alternative splicing results in inclusion of different combinations of YQXI and YXVP motifs in Dab1isoforms during development. Dab1variants with partial or complete loss of YQXI motifs are preferentially expressed at early developmental stages, whereas the commonly studied Dab1is predominantly expressed at late developmental stages. Expression of Dab1variants in 293T and Neuro2a cells reveals reduced levels or absence of tyrosine phosphorylationin variants that have lost one or both YQXI motifs. We further demonstrate that Dab1variants differ in their abilities to activate Src and recruit distinct SH2 domainsinvolved in specific downstream signaling pathways. We propose that coordinated expression of specific Dab1isoforms in different populations of cells in the developing brain contributes to precise neuronal migrationby modulating the activity of subsets of Dab1downstream effectors.