Vimentin intermediate filaments (VIFs), expressed in most mesenchymal and cancer cells, undergo dramatic reorganization during cell migration; however, the mechanism remains obscure. This study demonstrates that upon growth-factor stimulation, Src directly phosphorylates vimentin at Tyr117, leading to VIF disassembly into squiggles and particles at the cell edge during lamellipodia formation. The protein tyrosine phosphatase SHP2 counteracted the Src effects on VIF tyrosine phosphorylation and organization. VIFs formed by vimentin Y117D mutant were more soluble and dynamic than those formed by the wild-type and Y117F mutant. Increased expression of vimentin promoted growth-factor induced lamellipodia formation and cell migration, whereas the mutants suppressed both. The vimentin-induced increase in lamellipodia formation correlated with the activation of Rac and Vav2, with the latter associated with VIFs and recruited to the plasma membrane upon growth-factor stimulation. These results reveal a novel mechanism for regulating VIF dynamics through Src and SHP2 and demonstrate that proper VIF dynamics are important for Rac activation and cell migration.

在大多数间充质和癌细胞中表达的波形蛋白中间丝（VIF）在细胞迁移过程中会发生剧烈重组。但是，该机制仍然不清楚。这项研究表明，在生长因子刺激下，Src直接在Tyr117处磷酸化波形蛋白，从而导致层状脂蛋白形成过程中，VIF在细胞边缘分解为花粉和颗粒。蛋白质酪氨酸磷酸酶SHP2抵消了Src对VIF酪氨酸磷酸化和组织的影响。波形蛋白Y117D突变体形成的VIF比野生型和Y117F突变体形成的VIF更具溶解性和动态性。波形蛋白表达的增加促进了生长因子诱导的片状脂蛋白形成和细胞迁移，而突变体抑制了两者。波形蛋白诱导的lamellipodia形成的增加与Rac和Vav2的激活相关，后者与VIF相关，并在生长因子刺激下被募集到质膜上。这些结果揭示了一种通过Src和SHP2调节VIF动态的新颖机制，并证明适当的VIF动态对于Rac激活和细胞迁移很重要。