FAK-mediated phosphorylation at Y464 regulates p850 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. How-ever, the mechanisms by which p85s translocate into the nucleus remain elusive. Here, we describe the mechanism by which p850 translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p850 at the Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing the binding of p850 to KPNA1. PIK3R2/p850 is highly expressed in ccRCC samples and associated with overall survival of ccRCC patients. Nuclear but not cytoplasmic p850 performs oncogenic functions by repressing RB1 expres-sion and regulating the G1/S cell cycle transition. Nuclear p850 represses RB1 expression by stabilizing his -tone methyltransferase EZH1/EZH2 proteins. Last, the FAK inhibitor defactinib significantly suppresses the tumor growth of ccRCC with high p850 Y464 levels.

Automated summary

PI3K regulatory subunit p85 normally stabilizes and regulates catalytic subunit p110 in the cytoplasm. Recent studies reveal that p85 without p110 in the nucleus plays important roles in biological processes. However, the mechanisms of p85 translocation into the nucleus are still unclear. In this study, we describe the mechanism by which p850 translocates into the nucleus to promote ccRCC tumorigenesis. Phosphorylation of p850 at Y464 by FAK facilitates its nuclear translocation in the kidney through enhancing p850 binding to KPNA1. PIK3R2/p850 is highly expressed in ccRCC samples and is associated with overall survival of ccRCC patients. Nuclear, but not cytoplasmic, p850 functions as an oncogene by repressing RB1 expression and regulating the G1/S cell cycle transition. Nuclear p850 represses RB1 expression by stabilizing histone methyltransferase EZH1/EZH2 proteins. Lastly, the FAK inhibitor defactinib significantly suppresses tumor growth in ccRCC with high p850 Y464 levels.