Abstract 4932: mTORC1 regulates FAK phosphorylation

Abstract

Abstract The mammalian target of rapamycin (mTOR) functions as two complexes, mTORC1 and mTORC2, regulating cell growth, proliferation, survival, and motility. Previous studies have shown that mTORC2 controls cytoskeleton and cell motility. Recently, we have demonstrated that both mTORC1 and mTORC2 participate in the regulation of cell motility. Further studies have shown that rapamycin suppresses IGF-I induced cell motility by inhibiting S6K1-mediated phosphorylation of focal adhesion kinase (FAK), protein phosphatase 2A (PP2A)-mediated phosphorylation of Erk1/2, as well as expression and activities of the small GTPases (RhoA, Cdc42 and Rac1). As FAK plays a pivotal role in the regulation of cell motility, this study was set to determine how mTORC1 regulates the phosphorylation of FAK. By co-immunoprecipitation (co-IP) and immunoblotting (IB), we failed to detect a physical interaction between FAK and S6K1, suggesting that S6K1 may regulate the phosphorylation of FAK indirectly. Besides, knockdown of protein phosphatase 2A (PP2A) enhanced the phosphorylation of FAK and conferred resistance to rapamycin inhibition of IGF-I-stimulated phosphorylation of FAK. However, the co-IP/IB results revealed no direct interaction between FAK and PP2A either. Of interest, knockdown of protein phosphatase 5 (PP5) suppressed IGF-I stimulated cell motility, while knockdown of ATG13 increased IGF-I stimulated cell motility, suggesting that PP5 positively regulates cell motility, whereas ATG13 negatively regulates cell motility. It is well known that PP5 is an anti-apoptotic phosphatase, negatively regulating the ASK1-JNK cascade, and mTORC1 regulates autophagy through the ULK1/2-ATG13-FIP200 complex. Further research will determine how mTORC1 regulates cell motility in part by regulating the phosphorylation of FAK via S6K1, PP2A, PP5 and ATG13. (Supported by the Feist-Weiller Cancer Center, LSU Health Sciences Center, Shreveport, LA, USA.) Citation Format: Lin Li, Yan Luo, Lei Liu, Shile Huang. mTORC1 regulates FAK phosphorylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4932.