A Multiprotein Complex Negatively Regulates RAG GTPases and mTORC1

The protein kinase mTOR complex 1 (mTORC1) is a critical regulator of cell growth that is activated in response to energy and nutrient availability and deregulated in many human cancers. Amino acid stimulation induces mTORC1 signaling via the RAG GTPases, which bind GTP and recruit mTORC1 to the lysosomal membrane for activation. However, negative regulators of RAG GTPases have not yet been characterized. Bar-Peled and colleagues identified an 8-protein complex, referred to as GTPase-activating protein (GAP) activity toward RAGs (GATOR), which interacted with RAGs at the lysosomal surface and was composed of 2 subcomplexes, GATOR1 and GATOR2. Depletion of GATOR1 proteins including DEP domain containing 5 (DEPDC5) promoted constitutive localization of mTORC1 to the lysosomal membrane and blocked mTORC1 inactivation following amino acid withdrawal, suggesting that GATOR1 inhibits mTORC1 signaling. In contrast, knockdown of GATOR2 components such as missing oocyte, meiosis regulator, homolog (MIOS) prevented mTORC1 translocation to the lysosome and impaired amino acid–induced activation of mTORC1, indicating that the GATOR subcomplexes reciprocally regulate mTORC1-dependent amino acid sensing. GATOR1 functioned downstream of GATOR2 and upstream of RAGs and showed GAP activity toward RAGA and RAGB, thereby deactivating RAGs and inhibiting mTORC1 signaling. Intriguingly, inactivating mutations and truncating deletions in the genes encoding the GATOR1 proteins DEPDC5 and nitrogen permease regulator-like 2 (NPRL2) were detected in human glioblastoma and ovarian tumors and were associated with LOH events. GATOR1-deficient cancer cells exhibited hyperactivation of mTORC1 signaling that was insensitive to amino acid starvation and rescued by reexpression of DEPDC5 or NPRL2. Moreover, GATOR1 inactivation conferred enhanced sensitivity to rapamycin, suggesting that patients with GATOR1 mutations may benefit from treatment with mTORC1 inhibitors. These findings identify the tumor-suppressive GATOR complex as a negative regulator of RAG GTPases and amino acid sensing by mTORC1.

Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013;340:1100–6.