Dorsal ruffles enhance activation of Akt by growth factors

Yoshida, Sei; Pacitto, Regina; Sesi, Catherine; Kotula, Leszek; Swanson, Joel A.

doi:10.1242/jcs.220517

Cited by 23 publications

(15 citation statements)

References 62 publications

(102 reference statements)

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“…Consistent with this model, stimulation of macrophages with lower concentrations of M-CSF (140 pM), which generated lower levels of Akt phosphorylation than did receptor-saturating concentrations of M-CSF (6.9 nM), could be reduced by cytoskeleton inhibitors [65]. A similar relationship between the maximal levels of Akt phosphorylation responses and sensitivity to cytoskeletal inhibition was also observed in fibroblasts stimulated with PDGF, which generates a high maximal Akt response, and epidermal growth factor, which generates a low maximal Akt response [85]. These studies indicate that the actin cytoskeleton can amplify PI3K activity locally, and suggest that ruffles, macropinocytic cups or macropinosomes may serve as platforms for localized amplification of Akt phosphorylation by both PDK1 (generating pAkt(308)) and mTORC2 (pAkt(473)) [85].…”

Section: Macropinocytosis-associated Signals That Modulate Cell Metabmentioning

confidence: 93%

Macropinosomes as units of signal transduction

Swanson

Yoshida

2018

Phil. Trans. R. Soc. B

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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’.

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Section: Macropinocytosis-associated Signals That Modulate Cell Metabmentioning

confidence: 93%

Macropinosomes as units of signal transduction

Swanson

Yoshida

2018

Phil. Trans. R. Soc. B

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“…However, it is inhibited by increased membrane tension and enhanced by the extracellular clustering of GPI-anchored proteins, or glycoproteins or glycolipids by galectins, toxins and viruses [60]. Although at different signal strengths, macropinocytosis and EGFR-NCE are activated upon growth factor stimulation [33,61], and ADBE and UFE are triggered upon axon depolarization [62,63]. Only the uptake of IL2Rβ and γ chains, and that of inactive GPCRs occur through constitutive Clathrin-independent routes [64,65].…”

Section: Constitutive or Triggeredmentioning

confidence: 99%

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

Casamento

Boucrot

2020

Biochemical Journal

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Endocytosis mediates the cellular uptake of micronutrients and cell surface proteins. Clathrin-mediated endocytosis (CME) is the housekeeping pathway in resting cells but additional Clathrin-independent endocytic (CIE) routes, including Fast Endophilin-Mediated Endocytosis (FEME), internalize specific cargoes and support diverse cellular functions. FEME is part of the Dynamin-dependent subgroup of CIE pathways. Here, we review our current understanding of the molecular mechanism of FEME. Key steps are: (i) priming, (ii) cargo selection, (iii) membrane curvature and carrier formation, (iv) membrane scission and (v) cytosolic transport. All steps are controlled by regulatory mechanisms mediated by phosphoinositides and by kinases such as Src, LRRK2, Cdk5 and GSK3β. A key feature of FEME is that it is not constitutively active but triggered upon the stimulation of selected cell surface receptors by their ligands. In resting cells, there is a priming cycle that concentrates Endophilin into clusters on discrete locations of the plasma membrane. In the absence of receptor activation, the patches quickly abort and new cycles are initiated nearby, constantly priming the plasma membrane for FEME. Upon activation, receptors are swiftly sorted into pre-existing Endophilin clusters, which then bud to form FEME carriers within 10 s. We summarize the hallmarks of FEME and the techniques and assays required to identify it. Next, we review similarities and differences with other CIE pathways and proposed cargoes that may use FEME to enter cells. Finally, we submit pending questions and future milestones and discuss the exciting perspectives that targeting FEME may boost treatments against cancer and neurodegenerative diseases.

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“…Receptor tyrosine kinase signaling triggers dynamic remodeling of the cytoskeleton; in particular, activation of EGFR, PDGFR, IR, MET, and others leads to the rapid formation of actin-rich dorsal ruffles(DRs) at the plasma membrane (Abella et al, 2010; Hoon et al, 2012; Delos Santos et al, 2015; Yoshida et al, 2018). While not observed in all cells and contexts, DRs can serve to compartmentalize RTKs into spatially distinct membrane nanodomains for signaling.…”

Section: Localization Of Pi3k-akt Signaling Within Plasma Membrane Namentioning

confidence: 99%

“…While not observed in all cells and contexts, DRs can serve to compartmentalize RTKs into spatially distinct membrane nanodomains for signaling. In addition, DRs act in parallel to RTK internalization by CME as a clathrin-independent mechanism for RTK internalization by macropinocytosis (Orth et al, 2006; Abella et al, 2010; Gu et al, 2011; Yoshida et al, 2018). Internalization of RTKs by DRs through the macropinocytic pathway requires Arp2/3-dependent actin polymerization and PI3K; disruption of each results in attenuated DR formation and RTK macropinocytosis (Dharmawardhane et al, 2000).…”

Section: Localization Of Pi3k-akt Signaling Within Plasma Membrane Namentioning

confidence: 99%

Akt-ing Up Just About Everywhere: Compartment-Specific Akt Activation and Function in Receptor Tyrosine Kinase Signaling

Sugiyama

Fairn

Antonescu

2019

Front. Cell Dev. Biol.

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The serine/threonine kinase Akt is a master regulator of many diverse cellular functions, including survival, growth, metabolism, migration, and differentiation. Receptor tyrosine kinases are critical regulators of Akt, as a result of activation of phosphatidylinositol-3-kinase (PI3K) signaling leading to Akt activation upon receptor stimulation. The signaling axis formed by receptor tyrosine kinases, PI3K and Akt, as well as the vast range of downstream substrates is thus central to control of cell physiology in many different contexts and tissues. This axis must be tightly regulated, as disruption of PI3K-Akt signaling underlies the pathology of many diseases such as cancer and diabetes. This sophisticated regulation of PI3K-Akt signaling is due in part to the spatial and temporal compartmentalization of Akt activation and function, including in specific nanoscale domains of the plasma membrane as well as in specific intracellular membrane compartments. Here, we review the evidence for localized activation of PI3K-Akt signaling by receptor tyrosine kinases in various specific cellular compartments, as well as that of compartment-specific functions of Akt leading to control of several fundamental cellular processes. This spatial and temporal control of Akt activation and function occurs by a large number of parallel molecular mechanisms that are central to regulation of cell physiology.

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Dorsal ruffles enhance activation of Akt by growth factors

Cited by 23 publications

References 62 publications

Macropinosomes as units of signal transduction

Macropinosomes as units of signal transduction

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

Akt-ing Up Just About Everywhere: Compartment-Specific Akt Activation and Function in Receptor Tyrosine Kinase Signaling

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