Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Miączyńska, Marta

doi:10.1101/cshperspect.a009035

Cited by 111 publications

(103 citation statements)

References 176 publications

(193 reference statements)

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“…Endosomes are broadly recognized as the location for essential intracellular signaling events. Disruption of membrane traffic resulting in modifications of endosomal compartments lead to dramatic changes in the signaling cascades associated to the endosomes (26,33). Several pathways, including Akt (31), are known to require endosomal scaffolding.…”

Section: Discussionmentioning

confidence: 99%

Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment

Kravtsov

Mashukova

Forteza

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Microvillus inclusion disease (MVID) is an autosomal recessive condition resulting in intractable secretory diarrhea in newborns due to loss-of-function mutations in myosin Vb (Myo5b). Previous work suggested that the apical recycling endosomal (ARE) compartment is the primary location for phosphoinositide-dependent protein kinase 1 (PDK1) signaling. Because the ARE is disrupted in MVID, we tested the hypothesis that polarized signaling is affected by Myo5b dysfunction. Subcellular distribution of PDK1 was analyzed in human enterocytes from MVID/control patients by immunocytochemistry. Using Myo5b knockdown (kd) in Caco-2BBe cells, we studied phosphorylated kinases downstream of PDK1, electrophysiological parameters, and net water flux. PDK1 was aberrantly localized in human MVID enterocytes and Myo5b-deficient Caco-2BBe cells. Two PDK1 target kinases were differentially affected: phosphorylated atypical protein kinase C (aPKC) increased fivefold and phosohoprotein kinase B slightly decreased compared with control. PDK1 redistributed to a soluble (cytosolic) fraction and copurified with basolateral endosomes in Myo5b kd. Myo5b kd cells showed a decrease in net water absorption that could be reverted with PDK1 inhibitors. We conclude that, in addition to altered apical expression of ion transporters, depolarization of PDK1 in MVID enterocytes may lead to aberrant activation of downstream kinases such as aPKC. The findings in this work suggest that PDK1-dependent signaling may provide a therapeutic target for treating MVID.

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Section: Discussionmentioning

confidence: 99%

Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment

Kravtsov

Mashukova

Forteza

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…After internalization, many surface components remain stable and can signal from within the intracellular compartments (40). This has been linked to signal amplification.…”

Section: Discussionmentioning

confidence: 99%

“…This has been linked to signal amplification. Many internalized components are targeted to recycling endosomes and from there again to the cell surface or the tight junctions (40)(41)(42)(43)(44). The functions and the fate of internalized Nectin-1 remain to be identified.…”

Section: Discussionmentioning

confidence: 99%

Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells

Deschamps

Dogrammatzis

Mullick

et al. 2017

J Virol

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The Cbl E3 ligase has been linked to the down-modulation of surface signaling responses by inducing internalization of surface receptors. The adaptor protein CIN85 is a partner of Cbl that augments many of these interactions. Previously, an interaction was demonstrated between ICP0 and CIN85, which results in the removal of epidermal growth factor receptor (EGFR) from the surface of the infected cells with a concomitant attenuation of EGFR signaling. Here, we examined whether Cbl mediates the removal of the herpes simplex virus 1 (HSV-1) entry receptor Nectin-1 from the surface of infected cells. We found the following: (i) that Cbl, Nectin-1, and the viral glycoprotein D (gD) form a complex in infected cells; (ii) that during infection Nectin-1 is removed from the surface of the infected cells but is retained on the surface of cells that have been depleted of Cbl; and (iii) that in cells infected with a ΔICP0 mutant virus, Nectin-1 remained on the cell surface. Thus, Cbl is necessary but not sufficient for the removal of Nectin-1 from the cell surface. In addition, we observed that in Cbl-depleted cells there was enhanced entry after infection. These cells were susceptible to secondary infections by HSV-1. Viral entry in CIN85-depleted cells was only moderately enhanced compared to that in the Cbldepleted cells, suggesting that the Cbl-Nectin-1 interaction is likely the key to the downregulation of surface Nectin-1. The removal of the HSV-1 entry receptor Nectin-1 from the surface of the infected cells may be part of the strategy of the virus to efficiently spread to uninfected cells. IMPORTANCEThe Cbl E3 ligase suppresses surface signaling responses by inducing internalization of surface components. The targets of Cbl include such components as immune system receptors, growth factor receptors, adhesion, and cell-to-cell contact molecules. The immediate early protein ICP0 of herpes simplex virus 1 (HSV-1) interacts with CIN85, an adaptor protein that augments Cbl functions. The consequence of this interaction is the removal of the epidermal growth factor receptor (EGFR) from the surface of the infected cells with concomitant suppression of the EGF ligand signaling. The viral entry receptor Nectin-1 is also internalized during HSV-1 infection in a Cbl-dependent mechanism, and that increases the opportunity of the virus to spread to uninfected cells. The diversion of the Cbl/CIN85 endocytic machinery may be a strategy utilized by the virus to alter the cell surface pattern to prevent detrimental host responses.KEYWORDS Cbl E3 ligase, Nectin-1, endocytosis, ICP0, HSV-1, cell surface D uring herpes simplex virus 1 (HSV-1) infection, the immediate early protein ICP0 (infected cell protein 0) exerts two major sets of functions. First, ICP0 localizes in the nucleus immediately after its production and is involved in the blockage of the gene silencing machinery and provides an impediment to certain branches of innate immunity (1-4). After ICP0 accomplishes its major nuclear functions, it translocates to

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“…Secondly, the sorting to degradation or recycling determines the balance between termination and sustenance of signaling, respectively. Thirdly, compartmentalization of a receptor in different endosomal organelles may diversify its signaling output in time and space (Gonnord et al, 2012;Sigismund et al, 2012;Miaczynska, 2013;Irannejad et al, 2015;Villaseñor et al, 2016). Still, for most RTKs, the routes of endocytic trafficking and their impact on signaling remain poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling

Jastrzębski

Zdżalik-Bielecka

Mamińska

et al. 2017

Journal of Cell Science

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Platelet-derived growth factor receptor β (PDGFRβ) is a receptor tyrosine kinase which upon activation by PDGF-BB stimulates cell proliferation, migration and angiogenesis. Ligand binding induces intracellular signaling cascades but also internalization of the receptor, eventually resulting in its lysosomal degradation. However, endocytic trafficking of receptors often modulates their downstream signaling. We previously reported that internalization of PDGFRβ occurs via dynamin-dependent and -independent pathways but their further molecular determinants remained unknown. Here we show that, in human fibroblasts expressing endogenous PDGFRβ and stimulated with 50 ng/ml PDGF-BB, ligand-receptor uptake proceeds via the parallel routes of clathrin-mediated endocytosis (CME) and clathrin-independent endocytosis (CIE). CME involves the canonical AP2 complex as a clathrin adaptor, while CIE requires RhoA-ROCK, Cdc42 and galectin-3, the latter indicating lectinmediated internalization via clathrin-independent carriers (CLICs). Although different uptake routes appear to be partly interdependent, they cannot fully substitute for each other. Strikingly, inhibition of any internalization mechanism impaired activation of STAT3 but not of other downstream effectors of PDGFRβ. Our data indicate that multiple routes of internalization of PDGFRβ contribute to a transcriptional and mitogenic response of cells to PDGF.

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Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

Cited by 111 publications

References 176 publications

Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment

Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment

Cbl E3 Ligase Mediates the Removal of Nectin-1 from the Surface of Herpes Simplex Virus 1-Infected Cells

Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling

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