Abstract
Macropinosome formation occurs as a localized sequence of biochemical activities and associated morphological changes, which may be considered a form of signal transduction leading to the construction of an organelle. Macropinocytosis may also convey information about the availability of extracellular nutrients to intracellular regulators of metabolism. Consistent with this idea, activation of the metabolic regulator mechanistic target of rapamycin complex-1 (mTORC1) in response to acute stimulation by growth factors and extracellular amino acids requires internalization of amino acids by macropinocytosis. This suggests that macropinocytosis is necessary for mTORC1-dependent growth of metazoan cells, both as a route for delivery of amino acids to sensors associated with lysosomes and as a platform for growth factor-dependent signalling to mTORC1 via phosphatidylinositol 3-kinase (PI3K) and the Akt pathway. Because the biochemical signals required for the construction of macropinosomes are also required for cell growth, and inhibition of macropinocytosis inhibits growth factor signalling to mTORC1, we propose that signalling by growth factor receptors is organized into stochastic, structure-dependent cascades of chemical reactions that both build a macropinosome and stimulate mTORC1. More generally, as discrete units of signal transduction, macropinosomes may be subject to feedback regulation by metabolism and cell dimensions.This article is part of the Theo Murphy meeting issue ‘Macropinocytosis’.
Highlights
Macropinosomes are transient endocytic organelles which form spontaneously or in response to chemical or physical stimulation
Macropinocytosis may convey information about the availability of extracellular nutrients to intracellular regulators of metabolism. Consistent with this idea, activation of the metabolic regulator mechanistic target of rapamycin complex-1 in response to acute stimulation by growth factors and extracellular amino acids requires internalization of amino acids by macropinocytosis. This suggests that macropinocytosis is necessary for mTORC1-dependent growth of metazoan cells, both as a route for delivery of amino acids to sensors associated with lysosomes and as a platform for growth factor-dependent signalling to mTORC1 via phosphatidylinositol 3-kinase (PI3K) and the Akt pathway
Because the biochemical signals required for the construction of macropinosomes are required for cell growth, and inhibition of macropinocytosis inhibits growth factor signalling to mTORC1, we propose that signalling by growth factor receptors is organized into stochastic, structure-dependent cascades of chemical reactions that both build a macropinosome and stimulate mTORC1
Summary
Macropinosomes are transient endocytic organelles which form spontaneously or in response to chemical or physical stimulation. Macropinosomes originate from actin-rich, cell surface ruffles that reorganize into cups or circular dorsal ruffles, close at their distal margins and separate into the cytoplasm from the plasma membrane as vacuoles. Lysosomes, a process called ‘pyranhalysis’ [5] or ‘kissand-run’ [6] Such transient interactions can lead to molecular size-dependent, differential delivery of solute contents between macropinosomes and lysosomes (figure 2; electronic supplementary material, Video S2) [6,7]. Internalized solutes concentrate into lysosomes, where they may accumulate or be degraded by acid hydrolases Because of their large size and mechanism of maturation, macropinosomes can be considered as mechanical pumps that move water through cytoplasm and efficiently deliver extracellular solutes into lysosomes [7]. We propose that macropinosomes serve as discrete, independent units of signalling for cell growth, whose magnitude may be modulated by feedback stimulation or inhibition
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