Growth factor signaling to mTORC1 by amino acid-laden macropinosomes.

Publication Type:

Journal Article

Source:

J Cell Biol, Volume 211, Issue 1, p.159-72 (2015)

Keywords:

Amino Acids, Animals, Biological Transport, Endosomes, Fibroblasts, HEK293 Cells, Humans, Macrophage Colony-Stimulating Factor, Macrophages, Mechanistic Target of Rapamycin Complex 1, Mice, Inbred C57BL, Multiprotein Complexes, Pinocytosis, Platelet-Derived Growth Factor, Signal Transduction, TOR Serine-Threonine Kinases

Abstract:

The rapid activation of the mechanistic target of rapamycin complex-1 (mTORC1) by growth factors is increased by extracellular amino acids through yet-undefined mechanisms of amino acid transfer into endolysosomes. Because the endocytic process of macropinocytosis concentrates extracellular solutes into endolysosomes and is increased in cells stimulated by growth factors or tumor-promoting phorbol esters, we analyzed its role in amino acid-dependent activation of mTORC1. Here, we show that growth factor-dependent activation of mTORC1 by amino acids, but not glucose, requires macropinocytosis. In murine bone marrow-derived macrophages and murine embryonic fibroblasts stimulated with their cognate growth factors or with phorbol myristate acetate, activation of mTORC1 required an Akt-independent vesicular pathway of amino acid delivery into endolysosomes, mediated by the actin cytoskeleton. Macropinocytosis delivered small, fluorescent fluid-phase solutes into endolysosomes sufficiently fast to explain growth factor-mediated signaling by amino acids. Therefore, the amino acid-laden macropinosome is an essential and discrete unit of growth factor receptor signaling to mTORC1.