RT Journal Article SR Electronic T1 MAP4K3 inhibits Sirtuin-1 to repress the LKB1–AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201525 DO 10.26508/lsa.202201525 VO 6 IS 8 A1 Mary Rose Branch A1 Cynthia L Hsu A1 Kohta Ohnishi A1 Wen-Chuan Shen A1 Elian Lee A1 Jill Meisenhelder A1 Brett Winborn A1 Bryce L Sopher A1 J Paul Taylor A1 Tony Hunter A1 Albert R La Spada YR 2023 UL https://www.life-science-alliance.org/content/6/8/e202201525.abstract AB mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1–AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1–AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.