Kindlin-2 Tyrosine Phosphorylation and Interaction with Src Serve as a Regulatable Switch in the Integrin Outside-in Signaling Circuit [Signal Transduction]

September 18th, 2014 by Qu, H., Tu, Y., Guan, J.-L., Xiao, G., Wu, C.

Integrin-mediated cell-extracellular matrix (ECM) adhesion is critical for control of intracellular signaling; however, the mechanisms underlying this "outside-in" signaling are incompletely understood. Here we show that depletion of kindlin-2 impairs integrin "outside-in" signaling. Kindlin-2 is tyrosine phosphorylated upon cell-ECM adhesion. Furthermore, kindlin-2 binds Src in a cell-ECM adhesion regulatable fashion. At the molecular level, the kindlin-2-Src interaction is mediated by kindlin-2 F0 and Src SH2 and SH3 domains. Src activation increases kindlin-2 tyrosine phosphorylation and the kindlin-2-Src interaction. Conversely, inhibition of Src reduces kindlin-2 tyrosine phosphorylation and diminishes the kindlin-2-Src interaction. Finally, disruption of the kindlin-2-Src interaction, unlike depletion of kindlin-2, impairs neither cell-ECM adhesion nor cell-ECM adhesion-induced FAK Tyr397-phosphorylation. However, it markedly inhibits cell-ECM adhesion-induced paxillin tyrosine phosphorylation, cell migration and proliferation. These results suggest that kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch downstream of FAK in the integrin "outside-in" signaling circuit, relaying signals from cell-ECM adhesion to paxillin that control cell migration and proliferation.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Kindlin-2 Tyrosine Phosphorylation and Interaction with Src Serve as a Regulatable Switch in the Integrin Outside-in Signaling Circuit [Signal Transduction]