Integrin β1 transduces the signal for LY6D‐induced macropinocytosis and mediates senescence‐inducing stress‐evoked vacuole formation via FAK

Cellular senescence is a highly stable cell‐cycle arrest induced by DNA damage and various cellular stresses. Recently, we have revealed that lymphocyte antigen 6 complex, locus D (LY6D) is responsible for senescence‐inducing stress‐evoked vacuole formation through induction of Src family kinase (SFK)‐mediated macropinocytosis. However, the signaling molecule(s) transducing the macropinocytosis signal from extracellular LY6D to the cytoplasmic SFK are unknown. In this study, we identified integrin β1, a transmembrane signaling protein, as an interactor of LY6D by proteomic analysis and co‐immunoprecipitation assays. Inhibition of integrin β1 impaired LY6D‐induced macropinocytosis, and integrin β1 activated SFK through focal adhesion kinase to mediate macropinocytosis. These results indicate that integrin β1 is a crucial mediator of the LY6D‐induced vacuole formation in senescent cells. Our recent study has shown that lymphocyte antigen 6 complex, locus D (LY6D) is responsible for senescence‐inducing stress‐evoked vacuole formation through induction of macropinocytosis. Here, we identified integrin β1 as a binding partner of LY6D by a mass spectrometry‐based proteomic approach. In response to senescence‐inducing stimuli, the LY6D–integrin β1 interaction activates the focal adhesion kinase–Src family kinase pathway to induce macropinocytosis, leading to senescent cell survival.