Protein Kinase C Controls Microtubule-based Traffic but Not Proteasomal Degradation of c-Met

Kermorgant, Stéphanie; Zicha, Daniel; Parker, Peter J.

doi:10.1074/jbc.m302116200

Cited by 60 publications

(73 citation statements)

References 42 publications

(42 reference statements)

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“…Oncogenic, constitutively active c-Met forms, mutated in the kinase domain (M1268T or D1246N) [63][64][65][66] , undergo such shuttling, leading to persistent endosomal Rac1 signalling, actin reorganization, enhanced cell migration and metastasis 10 . c-Met wild type has mostly been described to get progressively degraded upon HGF stimulation 14 . However, the recycling of a proportion of internalized c-Met, under the control of Rab-coupling protein in various cells expressing mutant p53 (ref.…”

Section: Discussionmentioning

confidence: 99%

“…Whether a receptor can signal differently from distinct intracellular compartments and how this might influence cell behaviour is unknown. The receptor tyrosine kinase (RTK) and proto-oncogene c-Met clathrin and dynamin-dependent 10,11 endocytosis have been reported in several cell systems including MDCK 12,13 and HeLa cells 11,14 . c-Met endosomal signalling is required for full activation of ERK1/2 (ref.…”

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confidence: 99%

“…It was shown previously in HeLa cells that c-Met traffics from a peripheral endosomal compartment to a perinuclear endomembrane compartment along the microtubule network and that this is facilitated by PKCa catalytic activity 14 . A similar process operated in MDA-468 cells since PKCa inhibition by Gö6976 or knockdown by siRNA, or microtubule stabilization by Taxol, did not prevent c-Met internalization but impaired its post-endocytic trafficking: at 30 min of HGF stimulation, HGF/c-Met vesicles appeared more dispersed in the cytoplasm and did not accumulate efficiently in the Rab7-positive PNE (Fig.…”

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confidence: 99%

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Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

2014

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Receptor tyrosine kinases (RTKs) are increasingly recognized as having the capacity to signal post-internalization. Signalling outputs and/or duration, and subsequent cellular outcome, are thought to be distinct when emanating from endosomes compared with those from the plasma membrane. Here we show, in invasive, basal-like human breast cell models, that different mechanisms are engaged by the RTK c-Met in two different endosomes to control the actin cytoskeleton via the key migratory signal output Rac1. Despite an acute activation of Rac1 from peripheral endosomes (PEs), c-Met needs to traffic to a perinuclear endosome (PNE) to sustain Rac1 signalling, trigger optimal membrane ruffling, cell migration and invasion. Unexpectedly, in the PNE but not in the PE, PI3K and the Rac-GEF Vav2 are required. Thus we describe a novel endosomal signalling mechanism whereby one signal output, Rac1, is stimulated through distinct pathways by the same RTK depending on which endosome it is localized to in the cell.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

2014

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“…From the peripheral endosomes, MET traffics along the microtubule network and accumulates in a nondegradative perinuclear endomembrane compartment through a process that is promoted by PKCα 81,83 (Fig. 3b).…”

Section: Regulation Of Met Signallingmentioning

confidence: 99%

MET signalling: principles and functions in development, organ regeneration and cancer

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,060

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The MET tyrosine kinase receptor (also known as the HGF receptor) promotes tissue remodelling, which underlies developmental morphogenesis, wound repair, organ homeostasis and cancer metastasis, by integrating growth, survival and migration cues in response to environmental stimuli or cell-autonomous perturbations. The versatility of MET-mediated biological responses is sustained by qualitative and quantitative signal modulation. Qualitative mechanisms include the engagement of dedicated signal transducers and the subcellular compartmentalization of MET signalling pathways, whereas quantitative regulation involves MET partnering with adaptor amplifiers or being degraded through the shedding of its extracellular domain or through intracellular ubiquitylation. Controlled activation of MET signalling can be exploited in regenerative medicine, whereas MET inhibition might slow down tumour progression.Throughout embryogenesis, cells bud off from developing tissues and move outwards to shape and pattern the complex architecture of prospective organs 1 . A similar process occurs in adult life during wound healing and tissue repair, when lingering cells migrate into injury sites to recreate the pre-existing structures 2 . The acquisition of cell motility is necessary, but not sufficient, for this event. Cells that detach from their neighbours must elude anoikis, a form of apoptotic cell death that occurs when cells lose adhesion with the extracellular matrix 3 . Moreover, migratory cells undergo extensive mitotic divisions to produce 'founder populations', which settle in newly forming organs during development or colonize worn tissues during repair 4,5 . The normal phases of embryogenesis and organ regeneration strongly resemble the pathological process of tumour invasiveness: similarly to cells at the wound edge, cells at the tumour's leading front disrupt intercellular contacts and infiltrate the adjacent surroundings, where they resist anoikis and grow before lodging in the blood vessels for systemic dissemination 6 . This resemblance is not simply a biological correlate, it has a common mechanistic basis: cancer cells resurrect the latent schemes of cellular reorganization, which are usually confined to embryonic development and damaged adult organs, and leverage them to become competent for metastasization 7 . The activities -motility, survival and proliferation -that occur in developing, injured and neoplastic tissues embody a biological programme that is defined as 'invasive growth' 8 . This is triggered by extracellular stimuli that regulate the activity of several transcription factors that, in turn, modulate the expression of a number of proteins, ranging from cytoskeletal and cell-cell junctional components to cell cycle regulators and anti-apoptotic effectors 9, 10 . One major environmental inducer of invasive growth is hepatocyte growth factor (HGF, also known as scatter factor), the ligand for the MET tyrosine kinase receptor (also known as the HGF receptor) 11,12,13,14,15,16,17,18,19,20 (Box 1). ...

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“…After HGF treatment or Srcwt transfection of MDA-MB231 cells lacking E-cadherins, phospho -c-Src localized at the cell membrane, and Met was internalized, assuming a perinuclear disposition. The perinuclear compartment includes the late endosomes/lysosomes, i.e., the major route for Met degradation after proteasome delivery, as well as the Golgi, corresponding to a recycling compartment or containing newly synthesized Met (41). A functional significance for internalized Met might be suggested in the regulation of signal transduction pathways and nuclear gene expression, as reported in MCF-7 cells by us and other authors under different experimental conditions (3,42).…”

Section: Discussionmentioning

confidence: 80%

c-Src/Histone Deacetylase 3 Interaction Is Crucial for Hepatocyte Growth Factor–Dependent Decrease of CXCR4 Expression in Highly Invasive Breast Tumor Cells

Matteucci

Ridolfi

Maroni

et al. 2007

Molecular Cancer Research

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Hepatocyte growth factor (HGF), a cytokine of tumor microenvironment, exerts opposite effects on CXCR4 expression in MCF-7 (low invasive) and MDA-MB231 (highly invasive) breast carcinoma cells, and here, we show that completely different molecular mechanisms downstream of c-Src activation were involved. As experimental models, we used cells transfected with two CXCR4 promoter constructs and treated with HGF or cotransfected with c-Src wild-type (Srcwt) expression vector; phospho -c-Src formation was enhanced in both cell lines. In MCF-7 cells, consistent with activations of CXCR4Luc constructs after HGF treatment and Srcwt expression, Ets1 and nuclear factor-KB (NF-KB) transcription factors were activated. In contrast, in MDA-MB231 cells, CXCR4Luc construct, Ets1 and NF-KB activities decreased. The divergence point seemed to be downstream of HGF/c-Src and consisted in the interaction between c-Src and the substrate histone deacetylase 3 (HDAC3). Only in MDA-MB231 cells, HDAC3 level was enhanced in membranes and nuclei 30 min after HGF and colocalized/coimmunoprecipitated with phospho -c-Src and phosphotyrosine. Thus, the CXCR4 induction by HGF in MCF-7 cells required NF-KB and Ets1 activations, downstream of phosphoinositide-3-kinase/Akt, whereas in HGF-treated MDA-MB231 cells, HDAC3 activation via c-Src probably caused a reduction of transcription factor activities, such as that of NF-KB. These results indicate possible roles of HGF in invasive growth of breast carcinomas. By enhancing CXCR4 in low invasive tumor cells, HGF probably favors their homing to secondary sites, whereas by suppressing CXCR4 in highly invasive cells, HGF might participate to retain them in the metastatic sites. (Mol Cancer Res 2007;5(8):833 -45)

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Protein Kinase C Controls Microtubule-based Traffic but Not Proteasomal Degradation of c-Met

Cited by 60 publications

References 42 publications

Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

MET signalling: principles and functions in development, organ regeneration and cancer

c-Src/Histone Deacetylase 3 Interaction Is Crucial for Hepatocyte Growth Factor–Dependent Decrease of CXCR4 Expression in Highly Invasive Breast Tumor Cells

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