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Macropinocytosis, mTORC1 and cellular growth control
#MMPMID29119228
Yoshida S
; Pacitto R
; Inoki K
; Swanson J
Cell Mol Life Sci
2018[Apr]; 75
(7
): 1227-1239
PMID29119228
show ga
The growth and proliferation of metazoan cells are driven by cellular nutrient
status and by extracellular growth factors. Growth factor receptors on cell
surfaces initiate biochemical signals that increase anabolic metabolism and
macropinocytosis, an actin-dependent endocytic process in which relatively large
volumes of extracellular solutes and nutrients are internalized and delivered
efficiently into lysosomes. Macropinocytosis is prominent in many kinds of cancer
cells, and supports the growth of cells transformed by oncogenic K-Ras. Growth
factor receptor signaling and the overall metabolic status of the cell are
coordinated in the cytoplasm by the mechanistic target-of-rapamycin complex-1
(mTORC1), which positively regulates protein synthesis and negatively regulates
molecular salvage pathways such as autophagy. mTORC1 is activated by two distinct
Ras-related small GTPases, Rag and Rheb, which associate with lysosomal membranes
inside the cell. Rag recruits mTORC1 to the lysosomal surface where Rheb directly
binds to and activates mTORC1. Rag is activated by both lysosomal luminal and
cytosolic amino acids; Rheb activation requires phosphoinositide 3-kinase, Akt,
and the tuberous sclerosis complex-1/2. Signals for activation of Rag and Rheb
converge at the lysosomal membrane, and several lines of evidence support the
idea that growth factor-dependent endocytosis facilitates amino acid transfer
into the lysosome leading to the activation of Rag. This review summarizes
evidence that growth factor-stimulated macropinocytosis is essential for amino
acid-dependent activation of mTORC1, and that increased solute accumulation by
macropinocytosis in transformed cells supports unchecked cell growth.
|Amino Acids/metabolism
[MESH]
|Animals
[MESH]
|Cell Proliferation/*physiology
[MESH]
|Humans
[MESH]
|Intercellular Signaling Peptides and Proteins/metabolism
[MESH]
|Mechanistic Target of Rapamycin Complex 1/*metabolism
[MESH]
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