THE AMERICAN JOURNAL OF PATHOLOGY

Hau AM, Gupta S, Leivo MZ, Nakashima K, Macias J, Zhou W, Hodge A, Wulfkuhle J, Conkright B, Bhuvaneshwar K, Rao S, Madhavan S, Petricoin EF, 3rd and Hansel DE

Am J Pathol. 2019 Jun 11. pii: S0002-9440(19)30079-3.

DOI: 10.1016/j.ajpath.2019.05.010.

Abstract

The mammalian target of rapamycin (mTOR) and associated phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway is commonly up-regulated in cancer, including bladder cancer. mTOR complex 2 (mTORC2) is a major regulator of bladder cancer cell migration and invasion, but the mechanisms by which mTORC2 regulates these processes are unclear. A discovery mass spectrometry and reverse-phase protein array-based proteomics dual approach was used to identify novel mTORC2 phosphoprotein targets in actively invading cancer cells. mTORC2 targets included focal adhesion kinase, proto-oncogene tyrosine-protein kinase Src, and caveolin-1 (Cav-1), among others. Functional testing shows that mTORC2 regulates Cav-1 localization and dynamic phosphorylation of Cav-1 on Y14. Regulation of Cav-1 activity by mTORC2 also alters the abundance of caveolae, which are specialized lipid raft invaginations of the plasma membrane associated with cell signaling and membrane compartmentalization. Our results demonstrate a unique role for mTORC2-mediated regulation of caveolae formation in actively migrating cancer cells.