EGFR-RAS-MAPK signaling is confined to the plasma membrane and associated endorecycling protrusions

Surve, Sachin; Watkins, Simon C.; Sorkin, Alexander

doi:10.1083/jcb.202107103

Cited by 21 publications

(18 citation statements)

References 58 publications

(101 reference statements)

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“…Moreover, unlike ligand-dependent EGFR phosphorylation, p38-dependent EGFR phosphorylation did not trigger downstream signaling responses through ERK1/2. p38-dependent EGFR phosphorylation is associated with clathrin-mediated EGFR endocytosis ( 28 , 79 – 81 ), and the endocytosed receptor does not contribute to ERK1/2 signaling ( 82 ), suggesting therefore that p38 inhibition may retain EGFR on the plasma membrane where it can more effectively contribute to ERK1/2 signaling during candidalysin stimulation.…”

Section: Discussionmentioning

confidence: 99%

The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

et al. 2022

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The fungal pathogen Candida albicans secretes the peptide toxin candidalysin, which damages epithelial cells and drives an innate inflammatory response mediated by the epidermal growth factor receptor (EGFR) and mitogen-activated protein kinase (MAPK) pathways and the transcription factor c-Fos. In cultured oral epithelial cells, candidalysin activated the MAPK p38, which resulted in heat shock protein 27 (Hsp27) activation, IL-6 release, and EGFR phosphorylation without affecting the induction of c-Fos. p38 activation was not triggered by EGFR but by two nonredundant pathways involving MAPK kinases (MKKs) and the kinase Src, which differentially controlled p38 signaling outputs. Whereas MKKs mainly promoted p38-dependent release of IL-6, Src promoted p38-mediated phosphorylation of EGFR in a ligand-independent fashion. In parallel, candidalysin also activated the EGFR-ERK pathway in a ligand-dependent manner, resulting in c-Fos activation and release of the neutrophil-activating chemokines G-CSF and GM-CSF. In mice, early clearance events of oral C. albicans infection required p38 but not c-Fos. These findings delineate how candidalysin activates the pathways downstream of the MAPKs p38 and ERK that differentially contribute to immune activation during C. albicans infection.

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Section: Discussionmentioning

confidence: 99%

The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

et al. 2022

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“…However, we only observed a modest transient increase in ERK activation in retromer-depleted cells. Furthermore, recent studies also suggest that a small population of cell surface EGFR, rather than endosomal EGFR, is responsible for ERK activation [ 49 ]. Therefore, the contributions of endosomal EGFRs in retromer- and SNXs-depleted cells to EGFR signaling need to be fully characterized.…”

Section: Discussionmentioning

confidence: 99%

Multifaceted Roles of Retromer in EGFR Trafficking and Signaling Activation

Yang¹,

Feng²,

Li³

et al. 2022

Cells

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Mammalian retromer complex contributes to multiple early endosome-associated trafficking pathways whose origins are dependent on which sorting nexin (SNX) they are complexed with. In an attempt to dissect out the contribution of individual retromer–SNX complexes, we examined the trafficking of EGFR in detail within a series of KO cell line models. We demonstrated that the depletion of retromer subunit Vps35 leads to decreased EGFR protein levels in resting cells with enhanced association of EGFR with lysosomal compartments. Compared to control cells, the addition of EGF to Vps35 KO cells resulted in a reduced rate of EGFR degradation; AKT activation and cell prolferation rates were elevated, while ERK activation remained relatively unchanged. These observations are consistent with a prolonged temporal association of EGFR within early endosomes due to the inefficiency of early endosome-associated protein trafficking pathways or organelle maturation due to retromer absence. We did not fully delineate the discrete contributions from retromer-associated SNXs to the phenotypes observed from retromer Vps35 depletion. While each of the knock-outs of SNX1/2, SNX3, or SNX27 promotes the enhanced association of EGFR with early endosomal compartments, only the decreased EGF-mediated EGFR degradation was observed in SNX1/2 dKO cells, while the enhanced AKT activation was only increased in SNX3 KO or SNX27 KO cells. Despite this, each of the knock-outs showed increased EGF-stimulated cell proliferation rates.

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“…Such an understanding may help generate new hypotheses to explain apparently contradictory observations. For example, recent work from the Sorkin Lab has shown that RAS activation and ERK phosphorylation paradoxically remain dependent on EGFR activity after EGFR and RAS have become physically separated during endocytosis of the receptor (34,36,47).…”

Section: Discussionmentioning

confidence: 99%

“…This new understanding may help explain prior apparently contradictory observations. For example, recent work demonstrates that RAS activity and ERK phosphorylation paradoxically remain dependent on EGFR activity even after EGFR and RAS become physically separated due to EGFR endocytosis and membrane retention of RAS ( 40, 45, 52 ). Based on our work, GAB1-SHP2 complexes, generated by active endocytosed EGFR, may diffuse back to the cell membrane and thereby promote RAS activity.…”

Section: Discussionmentioning

confidence: 99%

“…We developed a computational model to predict the concentration of GAB1-SHP2 complexes as both a function of time and position for the first 5 minutes of EGFR activation following EGF binding within a spherical cell with an assumed radius of R = 10 μm. We limited our simulations to the first 5 minutes of EGFR activation since the peak of receptor activation and adaptor binding occurs within this early time period (34,35) and to avoid the intricacies involved in modeling EGFR internalization, trafficking, and degradation processes that become prominent after this time period (5,(36)(37)(38). The model considers cellular processes including EGFR phosphorylation, SFK activation, GAB1 phosphorylation, GAB1-SHP2 binding, and diffusion of cytosolic proteins, the full details of which are described in Model Development.…”

Section: Base Model Predictionsmentioning

confidence: 99%

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A spatially resolved EGFR signaling model predicts the length scale of GAB1-SHP2 complex persistence

Myers

Furcht

Deen

et al. 2021

Preprint

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Activation of receptor tyrosine kinases (RTKs) leads to the assembly of multi-membered protein complexes connected by phosphotyrosine-SH2 domain linkages. However, these linkages are relatively weak and reversible, which allows complex disassembly to occur on a time scale that permits phosphatases to dephosphorylate complex members and thereby regulate complex persistence. Here, we generated a computational reaction-diffusion model to predict the length scale over which membrane-bound RTKs can regulate the maintenance of such protein complexes through the intermediary action of diffusible cytoplasmic kinases. Specifically, we show that the RTK EGFR can activate SRC family kinases (SFKs) to maintain the association of SHP2 with phosphorylated GAB1, which activates SHP2, throughout the entire cell volume. This finding is dependent on the ability of SFKs to be activated by EGFR at the plasma membrane and subsequently diffuse through the cytosol, as altering the model topology to permit only SFK activation at the plasma membrane reduces the length scale of GAB1-SHP2 association. Modifying the model topology to neglect GAB1 binding to cytosolic and EGFR-bound GRB2 had little effect on this length scale. Indeed, a model sensitivity analysis identified protein diffusion, SFK inactivation, and GAB1 dephosphorylation as the processes that most strongly control the distance over which GAB1-SHP2 persists distal from EGFR. A model scaling analysis likewise predicted that the length scale of GAB1-SHP2 association is greatly extended compared to that of SFK activation and that GAB1-SHP2 complexes persist throughout the cell volume. Furthermore, the same processes identified in the model sensitivity analysis appeared in the length scale estimate for GAB1-SHP2 association. In vitro experiments using proximity ligation assay and immunofluorescence against GAB1-SHP2 and EGFR, respectively, suggested that GAB1-SHP2 complexes are distributed throughout cells and exist distally from EGFR during EGF stimulation. Overall, our results suggest that GAB1-SHP2 complexes—and thus active SHP2—can persist distally from EGFR due to re-phosphorylation of GAB1 throughout the cytosol by EGFR-activated SFKs.

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EGFR-RAS-MAPK signaling is confined to the plasma membrane and associated endorecycling protrusions

Cited by 21 publications

References 58 publications

The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

The Candida albicans toxin candidalysin mediates distinct epithelial inflammatory responses through p38 and EGFR-ERK pathways

Multifaceted Roles of Retromer in EGFR Trafficking and Signaling Activation

A spatially resolved EGFR signaling model predicts the length scale of GAB1-SHP2 complex persistence

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