Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
J Cell Biol. 2019 Jan 7;218(1):285-298. doi: 10.1083/jcb.201804106. Epub 2018 Nov 7.
Differential inclusion or skipping of microexons is an increasingly recognized class of alternative splicing events. However, the functional significance of microexons and their contribution to signaling diversity is poorly understood. The Met receptor tyrosine kinase (RTK) modulates invasive growth and migration in development and cancer. Here, we show that microexon switching in the Arf6 guanine nucleotide exchange factor cytohesin-1 controls Met-dependent cell migration. Cytohesin-1 isoforms, differing by the inclusion of an evolutionarily conserved three-nucleotide microexon in the pleckstrin homology domain, display differential affinity for PI(4,5)P (triglycine) and PI(3,4,5)P (diglycine). We show that selective phosphoinositide recognition by cytohesin-1 isoforms promotes distinct subcellular localizations, whereby the triglycine isoform localizes to the plasma membrane and the diglycine to the leading edge. These data highlight microexon skipping as a mechanism to spatially restrict signaling and provide a mechanistic link between RTK-initiated phosphoinositide microdomains and Arf6 during signal transduction and cancer cell migration.
外显子的差异包含或跳过是一种越来越被认可的可变剪接事件类别。然而，微外显子的功能意义及其对信号多样性的贡献还了解甚少。Met 受体酪氨酸激酶（RTK）在发育和癌症中调节侵袭性生长和迁移。在这里，我们表明，Arf6 鸟嘌呤核苷酸交换因子细胞溶质素-1 中的微外显子切换控制 Met 依赖性细胞迁移。细胞溶质素-1 同工型通过在pleckstrin 同源结构域中包含一个进化上保守的三核苷酸微外显子而有所不同，显示出对 PI(4,5)P (三甘氨酸) 和 PI(3,4,5)P (二甘氨酸) 的不同亲和力。我们表明，细胞溶质素-1 同工型对磷酸肌醇的选择性识别促进了不同的亚细胞定位，其中三甘氨酸同工型定位于质膜，二甘氨酸同工型定位于前缘。这些数据突出了外显子跳过作为一种空间限制信号的机制，并为 RTK 引发的磷酸肌醇微区室与信号转导和癌细胞迁移期间的 Arf6 之间提供了一种机制联系。
