FAK-mediated phosphorylation at Y464 regulates p85β nuclear translocation to promote tumorigenesis of ccRCC by repressing RB1 expression

PI3K regulatory subunit p85s normally stabilizes and regulates catalytic subunit p110s in the cytoplasm. Recent studies show that p110-free p85s in the nucleus plays important roles in biological processes. However, the mechanisms by which p85s translocate into the nucleus remain elusive. Here, we describe the mechanism by which p85β translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p85β at the Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing the binding of p85β to KPNA1. PIK3R2/p85β is highly expressed in ccRCC samples and associated with overall survival of ccRCC patients. Nuclear but not cytoplasmic p85β performs oncogenic functions by repressing RB1 expression and regulating the G1/S cell cycle transition. Nuclear p85β represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Last, the FAK inhibitor defactinib significantly suppresses the tumor growth of ccRCC with high p85β Y464 levels.