Macropinocytosis, mTORC1 and cellular growth control

Area of Science:

• Cell Biology
• Molecular Biology
• Cancer Research

Background:

• Cellular growth and proliferation depend on nutrient availability and growth factors.
• Growth factor receptors trigger signaling pathways that enhance metabolism and macropinocytosis, a process for internalizing extracellular nutrients.
• Macropinocytosis is prevalent in cancer cells and supports oncogenic K-Ras-driven growth.

Purpose of the Study:

• To review the evidence linking growth factor-stimulated macropinocytosis to the activation of mechanistic target-of-rapamycin complex-1 (mTORC1).
• To elucidate the role of macropinocytosis in supplying amino acids for mTORC1 activation and supporting cancer cell proliferation.

Main Methods:

• Literature review of studies on cell signaling, nutrient sensing, and endocytosis.
• Analysis of the coordination between growth factor receptors, macropinocytosis, and mTORC1 signaling.
• Examination of the roles of Rag and Rheb GTPases in mTORC1 activation at the lysosomal membrane.

Main Results:

• Growth factor signaling enhances macropinocytosis, facilitating the internalization of extracellular solutes and nutrients.
• Macropinocytosis delivers essential amino acids into lysosomes, activating the Rag GTPase.
• Activated Rag and Rheb GTPases converge at the lysosome to activate mTORC1, promoting protein synthesis and cell growth.

Conclusions:

• Growth factor-stimulated macropinocytosis is essential for the amino acid-dependent activation of mTORC1.
• Increased nutrient uptake via macropinocytosis in transformed cells contributes to uncontrolled proliferation.
• Targeting macropinocytosis could be a strategy to inhibit cancer cell growth.