Macropinocytosis, mTORC1 and cellular growth control

Abstract

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.

Dorsal Ruffles Enhance Activation of Akt by Growth Factors

“…This and previous studies of signaling to Akt (Yoshida et al, 2015b, Pacitto et al, 2017, Erami et al, 2017) support a concept in which cells amplify weak PI3K signals using confined subregions of plasma membrane that limit lateral diffusion of PIP3 in the membrane (Kay et al, 2018). Cytoskeleton-dependent amplification of Akt signaling may reflect the normal behavior of growing cells, in which constant concentrations of growth factors trigger stochastic, localized signal cascades (Yoshida et al, 2009, Yoshida et al, 2018. Cytoskeleton-independent signaling could be an aberrant consequence of receptor overexpression or dysregulation of PI3K.…”

“…Macropinocytosis is a cellular process of solute endocytosis induced by growth factors, chemokines, and various other stimuli (Swanson, 2008, Egami et al, 2014, Buckley and King, 2017, Yoshida et al, 2018. In macrophages, stimulation with macrophage-colony stimulating factor (M-CSF) or the chemokine CXCL12 elicits membrane ruffles, which form cup-shaped structures that close into large endocytic vesicles called macropinosomes (Yoshida et al, 2009, Yoshida et al, 2015a, Pacitto et al, 2017.…”

“…mTORC1 is activated at lysosomal membranes by two small GTPases, Rag and Rheb (Saito et al, 2005, Sancak et al, 2010, Betz and Hall, 2013, Saxton and Sabatini, 2017. Macropinosomes induced by receptor activation deliver extracellular nutrients into lysosomes, where lysosome-associated membrane protein complexes detect the increased luminal concentrations of amino acids and trigger the activation of Rag GTPases (Yoshida et al, 2015b, Yoshida et al, 2018, Zoncu et al, 2011. Activated Rag recruits mTORC1 from cytosol to lysosomes (Sancak et al, 2008, Sancak et al, 2010.…”

Meridianin C inhibits the growth of YD‐10B human tongue cancer cells through macropinocytosis and the down‐regulation of Dickkopf‐related protein‐3

“…Macropinocytosis can be activated and exploited in normal and cancer cells to confer a cell growth/survival advantage . By contrast, hyper‐stimulation of macropinocytosis might play a critical role in the cytotoxicity of normal and cancer cells .…”

“…Macropinocytosis can be activated and exploited in normal and cancer cells to confer a cell growth/survival advantage. [34][35][36] By contrast, hyper-stimulation of macropinocytosis might play a critical role in the cytotoxicity of normal and cancer cells. 35,37 Notably, there are a number of several natural or synthetic chemicals that have anti-tumour effects through stimulation of macropinocytosis.…”