Yoon et al. describe how two signaling pathways combine to ensure that cells only grow when sufficient nutrients are available.

The kinase complex mTORC1 stimulates protein synthesis in response to various growth factors, as long as the cell's supply of amino acids is plentiful. If enough nutrients are available, the Rag family of small GTPases helps deliver mTORC1 to lysosomes, where the kinase complex is activated. The phosphatidylinositol 3-kinase hVps34 is also thought to promote mTORC1 activity in the presence of amino acids, but how this enzyme controls mTORC1 is unclear.

Yoon et al. found that hVps34 stimulated the activity of phospholipase D1 (PLD1), an enzyme that activates mTORC1 by generating phosphatidic acid. Amino acids boosted PLD1 activity in cells as long as hVps34 was active. PLD1, in turn, was required for amino acids and hVps34 to stimulate mTORC1. hVps34 activated PLD1 by producing phosphatidylinositol 3-phosphate, which bound to a lipid-binding PX domain in PLD1.

Amino acids and hVps34 also stimulated PLD1's translocation to lysosomes, a necessary step for mTORC1 activation. PLD1 was still delivered to lysosomes in cells lacking Rag GTPases, however, indicating that the two amino acid–sensing pathways—hVps34 and Rag—act in parallel to bring PLD1 and mTORC1 together when nutrient levels are high enough to permit growth. Senior author Jie Chen now wants to investigate where in the cell hVps34 stimulates PLD1 and to determine why lysosomes are the designated site of mTORC1 activation.

et al
J. Cell Biol.