mTORC1 controls cell proliferation by coordinating antagonistic extracellular regulated protein kinase and p38 MAPK signaling

mTOR is a sensor of nutrients/growth factors and a prominent pro-growth signaling molecule; it is highly activated in various tumors and represents a chemotherapeutic target. While mTOR-fueled anabolic processes are believed to drive cell proliferation, we now provide multiple lines of evidence that mTOR controls cell proliferation via two antagonistic MAPK pathways. Ablation of Tsc1, encoding an mTOR suppressor, in renal tubular cells led to overproliferation and cystogenesis, which is accompanied by activation of both pro- and anti-proliferation pathways. mTOR activation increases MEK1 expression and ERK activation and Mek1 ablation or inhibition rescues tubular overgrowth via regulating Myc and cyclin expression. mTOR activation also increases MKK6 expression and p38MAPK activation and ablation of p38?-encoding gene leads to tumorigenesis by suppressing p53 and p16 expression. Thus, mTOR utilizes MEK1-ERK to drive cell proliferation and MKK6-p38MAPK to protect cell from oncogenesis concurrently, identifying MEK1-ERK as a potential target to treat mTOR-induced hyperplasia.