mTORC1 regulates nutrient access in Ras-mediated tumors

Cheong, Heesun

doi:10.18632/aging.100974

Cited by 1 publication

(2 citation statements)

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“…Moreover, the growth of cells in nutrient-poor regions of pancreatic tumors was supported by scavenging of extracellular proteins [ 119 ]. Other groups have reported that H-Ras(G12V)-induced macropinocytosis is necessary for albumin-dependent cell growth of MEFs and that inhibition of mTORC1 activation increases the rate of macropinocytosis in carcinoma cells (MIA PaCa-2 K Ras mutant) [ 41 , 42 ]. Additionally, inhibition of DOCK1, a Rac-activating protein required for macropinocytosis, reduces survival of Ras-driven cell growth [ 120 ].…”

Section: Pathogenic Functions Of Macropinocytosis In K-ras-induced Camentioning

confidence: 99%

“…Macropinocytosis and mTORC1 activation share many common mechanisms for their induction, and recent studies have demonstrated that macropinocytosis contributes to cell growth by stimulating mTORC1 activity [ 2 , 7 , 8 , 38 – 42 ]. This review compares the molecular mechanisms underlying the induction of macropinocytosis and mTORC1 activity, and discusses crucial roles of macropinocytosis in the assimilation of nutrients for cell growth.…”

Section: Introductionmentioning

confidence: 99%

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Macropinocytosis, mTORC1 and cellular growth control

Yoshida

Pacitto

Inoki

et al. 2017

Cell. Mol. Life Sci.

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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.

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