Macropinocytosis is a form of endocytosis that originates from actin-dependent membrane ruffles, which turn from cup-shaped structures into macropinosome vesicles. Additionally, stimulation with platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) triggers an alternative pathway that forms circular dorsal ruffles (CDRs). Ultimately, this allows for activation of the mechanistic target of rapamycin complex-1 (mTORC1) for cell growth and metabolism control in response to stimuli. Signal transduction from the plasma membrane through the cytoplasm relies on activity of phosphatidylinositol 3-kinase (PI3K), its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and phosphorylation of the serine/threonine kinase Akt (pAkt). In their Research Article (Yoshida et al., 2018), Sei Yoshida, Joel Swanson and colleagues assess the contribution of CDRs to Akt phosphorylation following PDGF and EGF stimulation. They show that phosphorylated Akt peaks coincidentally with the appearance of CDRs. Furthermore, microtubule depolymerisation inhibited CDR formation and prevented Akt phosphorylation as a response to stimulation with EGF, but not PDGF. The authors could identify localizations of Akt, pAkt and PIP3 in both ruffles and CDRs. Importantly, CDRs appear to enable local signal amplification for pAkt when receptor-mediated PI3K stimulation is low. Taken together, these results highlight roles for plasma membrane domains and macropinocytosis in signal transduction for growth factor signalling towards mTORC1.
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