Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing
to its central role in controlling cell growth, proliferation, and metabolism. Regulation
of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens,
nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP
ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1
through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly,
we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2
but also in the absence of AMPK. Consistent with these observations, in two distinct
preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling
in an AMPK-independent manner. We found that the ability of biguanides to inhibit
mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.