Rac1 Regulates the Activity of mTORC1 and mTORC2 and Controls Cellular Size

SummaryMammalian target of rapamycin (mTOR) is a serine/threonine kinase that exists in two separate complexes, mTORC1 and mTORC2, that function to control cell size and growth in response to growth factors, nutrients, and cellular energy levels. Low molecular weight GTP-binding proteins of the Rheb and Rag families are key regulators of the mTORC1 complex, but regulation of mTORC2 is poorly understood. Here, we report that Rac1, a member of the Rho family of GTPases, is a critical regulator of both mTORC1 and mTORC2 in response to growth-factor stimulation. Deletion of Rac1 in primary cells using an inducible-Cre/Lox approach inhibits basal and growth-factor activation of both mTORC1 and mTORC2. Rac1 appears to bind directly to mTOR and to mediate mTORC1 and mTORC2 localization at specific membranes. Binding of Rac1 to mTOR does not depend on the GTP-bound state of Rac1, but on the integrity of its C-terminal domain. This function of Rac1 provides a means to regulate mTORC1 and mTORC2 simultaneously.

Graphical AbstractFigure optionsDownload high-quality image (221 K)Download as PowerPoint slideHighlights
► The effects of Rac 1 on cell size are mediated through mTOR
► Rac1 is required for both mTORC1 and mTORC2 activity
► Rac1 regulates mTORC1 and mTORC2 independent of its binding to GTP/GDP
► Rac1 interacts directly with mTOR through the Rac1 C-terminal region