细胞迁移受体蛋白MIG-13/LRP12区域性活化的机制研究

Directional cell migration requires the establishment and maintenance of the polarity. Despite remarkable progresses in understanding polarity establishment, relatively little is known regarding the maintenance of a protrusive leading edge and a contractile rear. Our previous study reported that the C. elegans transmembrane protein LRP12 homolog, MIG-13, acted through ABL-1-WAVE and SEM-5-WASP two parallel pathways to stimulate Arp2/3-mediated actin polymerization at the leading edge, thereby establishing the polarity. However it remains elusive how to maintain the stability of polarity during cell migration. Our preliminary results showed that a tyrosine kinase SRC-1 phosphorylates MIG-13 and promotes its activity at the leading edge, whereas a receptor-like tyrosine phosphatase PTP-3 is essential for the polarity maintenance in the migrating Q cells. We found that this phosphatase is specifically enriched in the rear. Our biochemical analyses uncovered an antagonism between SRC-1 kinase and PTP-3 phosphatase on activating receptor protein MIG-13. We aim to further explore the mechanism underlying MIG-13 signaling pathway during directional cell migration. We expect that our study will identify a novel mechanism that maintains cell polarity during directional cell migration.

定向细胞迁移的进行需要在迁移方向上建立和维持极性结构的稳定，大量的研究报导了极性结构的分子组成及建立机制，然而极性结构如何被持续稳定并不清楚。申请人先前的工作揭示跨膜蛋白LRP12的线虫同源蛋白MIG-13通过ABL-1-WAVE和SEM-5-WASP两条平行通路在Q细胞前导端激活Arp2/3复合体，促进微丝骨架的极性组装。申请人拟深入研究MIG-13/LRP12激活的极性结构是如何在细胞迁移过程中被稳定的机制，初步结果表明：酪氨酸激酶SRC-1通过磷酸化MIG-13的胞内段开启下游信号通路，从而建立极性结构；受体酪氨酸磷酸酶PTP-3特异性的定位于Q细胞的两侧及尾部，体外生化实验揭示PTP-3可以去磷酸化MIG-13，对维持迁移极性结构的稳定至关重要。本课题拟通过探究SRC-1和PTP-3对受体蛋白MIG-13的时空调控，加深对迁移细胞极性结构建立与维持的理解。