Lundgren T Kalle, Stenqvist Anna, Scott Rizaldy P, Pawson Tony, Ernfors Patrik
Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
J Cell Biochem. 2008 Jun 1;104(3):879-94. doi: 10.1002/jcb.21671.
During development neural progenitor cells migrate with extraordinary precision to inhabit tissues and organs far from their initial position. Little is known about the cellular basis for directional guidance by tyrosine kinase receptors (RTKs). RET is a RTK with important functions in guiding the migration of neuronal cells, and RET dysregulation leads to clinical disease such as agangliosis of the colon. We show here that RET migration in neuroepitheliomal and non-neuronal cells is elicited by the activation of specific signaling pathways initiated by the competitive recruitment of the FRS2 adaptor molecule to tyrosine 1062 (Y1062) in RET. FRS2 selectively recruited RET to focal complexes and led to activation of SRC family kinases and focal adhesion kinase (FAK). Activation of SRC depended on its direct interaction with RET at a different intracellular tyrosine (Y981) and activation of molecular signaling from these two separate sites in concert regulated migration. Our data suggest that an important function for FRS2 is to concentrate RET in membrane foci, leading to an engagement of specific signaling complexes localized in these membrane domains.
在发育过程中，神经祖细胞以极高的精度迁移，以占据远离其初始位置的组织和器官。关于酪氨酸激酶受体（RTK）进行定向引导的细胞基础，我们所知甚少。RET是一种RTK，在引导神经元细胞迁移中具有重要功能，RET失调会导致临床疾病，如结肠无神经节症。我们在此表明，神经上皮细胞和非神经元细胞中RET的迁移是由特定信号通路的激活引发的，该信号通路由FRS2衔接分子竞争性募集到RET中的酪氨酸1062（Y1062）启动。FRS2选择性地将RET募集到粘着斑复合体，并导致SRC家族激酶和粘着斑激酶（FAK）的激活。SRC的激活取决于其在不同细胞内酪氨酸（Y981）处与RET的直接相互作用，并且来自这两个不同位点的分子信号激活协同调节迁移。我们的数据表明，FRS2的一个重要功能是将RET集中在膜焦点上，导致定位于这些膜结构域的特定信号复合体的参与。
