Macropinosomes as units of signal transduction

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’.

The breadth of macropinocytosis research

“…Moreover, unlike free-living amoebae, which must be wary of the environmental molecules they absorb, metazoan cells may acquire extracellular nutrients entirely by transport proteins in the plasma membrane, obviating the need for ingestion of nutrients by endocytosis. Despite this, growth factor receptor signalling to the metabolic regulator mechanistic target-of-rapamycin complex-1 (mTORC1) often requires macropinocytosis of extracellular amino acids or the actin-rich macropinocytic cup domains of plasma membrane, which suggests that macropinocytosis remains essential to growth control in mammalian cells (see the article by Swanson & Yoshida [33]). Thus, although macropinocytosis supports cell growth when upregulated by mutations, the ubiquity of macropinocytosis and its requirement for the growth of all metazoan cells remain uncertain.…”

The membrane binding and deformation property of vaccinia virus K1 ankyrin repeat domain protein

“…In virus infection, vaccinia viruses internalize into host cells through micropinocytosis, which is one of endocytoses to mediate uptake of extracellular fluid (Rizopoulos et al, ). In the early stage of macropinocytosis, PI(4,5)P 2 is transiently increased (Swanson & Yoshida, ; Welliver & Swanson, ). Although the localization of K1 protein is not apparent in vaccinia virus, K1 protein may be involved in the entry of vaccinia virus through macropinosomes by the binding to PI(4,5)P 2 and its membrane deformation.…”

The structural dynamics of macropinosome formation and PI3-kinase-mediated sealing revealed by lattice light sheet microscopy

“…This central macrophage function enables immune surveillance, clearing of debris, and sampling of the local environment for the presence of pathogen-or damage-associated molecular patterns, cytokines, growth factors, nutrients, and other soluble cues [1][2][3][4][5][6] . Macropinosomes also serve as platforms to integrate this diverse information and to activate a variety of signaling pathways [7][8][9][10] . The major macrophage growth factor, colony-stimulating factor-1 (CSF-1), stimulates macropinocytosis and contributes to ligand-dependent modulation of CSF-1 receptor signaling 9 .…”