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

Molecular and Cellular Biology
Zhihua GaoRoseline Godbout

Abstract

Disabled-1 (Dab1) plays a key role in reelin-mediated neuronal migration during brain development. Tyrosine phosphorylation of Dab1 at 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 Dab1 downstream effectors remain poorly understood. Here, we show that alternative splicing results in inclusion of different combinations of YQXI and YXVP motifs in Dab1 isoforms during development. Dab1 variants with partial or complete loss of YQXI motifs are preferentially expressed at early developmental stages, whereas the commonly studied Dab1 is predominantly expressed at late developmental stages. Expression of Dab1 variants in 293T and Neuro2a cells reveals reduced levels or absence of tyrosine phosphorylation in variants that have lost one or both YQXI motifs. We further demonstrate that Dab1 variants differ in their abilities to activate Src and recruit distinct SH2 domains involved in specific downstream signaling pathways. We propose that coordinated expression of specific Dab1 isoforms in different populations of cells in the developing brain contributes to precise neuronal migration by...Continue Reading

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Citations

Oct 12, 2012·Cellular and Molecular Life Sciences : CMLS·Zhihua Gao, Roseline Godbout
Dec 10, 2013·Biology of the Cell·María D Vázquez-CarreteroAnunciación A Ilundain
Jun 22, 2014·Trends in Genetics : TIG·Hong-Dong LiYuanfang Guan
Feb 28, 2018·Frontiers in Molecular Biosciences·Chun-Hao SuWoan-Yuh Tarn
Mar 28, 2018·Molecular and Cellular Biology·Dhananjaya DWoan-Yuh Tarn
Apr 21, 2016·Nature Reviews. Neuroscience·Celine K VuongSika Zheng
Apr 16, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Karin FredrikssonStewart J Levine
Feb 13, 2021·International Journal of Molecular Sciences·Paula DlugoszJohannes Nimpf

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