Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway ( ). In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling ( ). In the presence of abundant amino acids, the GATOR1 complex is ubiquitinated and inhibited by GATOR2 (, ). Within the GATOR1 complex, NPRL2 constitutes the catalytic subunit that mediates the GAP activity (, ).
Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling . Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues . May act as a tumor suppressor . Suppresses cell growth and enhances sensitivity to various anticancer drugs .
Subcellular locations: Lysosome membrane
Localization to lysosomes is mediated by the KICSTOR complex and is amino acid-independent.
Most abundant in skeletal muscle, followed by brain, liver and pancreas, with lower amounts in lung, kidney, placenta and heart. Expressed in the frontal lobe cortex as well as in the temporal, parietal, and occipital lobes (, ). Expressed in most lung cancer cell lines tested.