RhoA regulates the mechanistic target of rapamycin complex 1 (mTORC1)

Abstract

The mTORC1 signaling pathway plays a vital role in integrating signals generated by hormones and nutrients to control cell growth and metabolism. The point of integration of many of the input signals from hormones is the GTPase activating protein complex TSC1/2 that acts to repress the mTORC1‐stimulatory activity of the small GTPase Rheb. In addition to its role in repressing Rheb activity, TSC1/2 has also been reported to interact with other GTPases, including members of the Rho family. Thus, the purpose of the present study was to test the hypothesis that one or more members of the Rho GTPase family modulate signaling through mTORC1. Phosphorylation of p70S6K1 on T389, a direct target of mTORC1, was used as an index of mTORC1 activity. Inhibition of Rho GTPase activity by C3 toxin enhanced p70S6K1(T389) phosphorylation 86 ± 8% (p<0.01) while activation of Rho GTPase activity repressed it 24 ± 1% (p<0.05). Moreover, p70S6K1(T389) phosphorylation was increased in response to either siRNA‐mediated repression of RhoA expression or expression of an inactive RhoA variant. In contrast, expression of constitutively active RhoA blunted both insulin and leucine‐induced stimulation of p70S6K(T389) phosphorylation by 28% to 31% (p<0.05). Overall, the results are consistent with the novel idea that the RhoA‐GTP complex represses and the RhoA‐GDP complex activates mTORC1 signaling. (Supported by grants DK‐15658 and DK‐13499)