A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein

Lamorte, Louie; Kamikura, Darren M.; Park, Morag

doi:10.1038/sj.onc.1203977

Cited by 54 publications

(55 citation statements)

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“…However, blocking a single network node is sufficient to perturb cellular responses, indicating that the targeted inhibition of a specific signalling pathway cannot be compensated for by other, still active, regulatory tiers. This is in line with the well-established observation that obstruction of individual MET-dependent pathways adversely affects tumour growth, survival and migration in various cancer cell types and under different experimental settings 37,48,50,56,57,58,70,71,72,76,139 . For example, the integrity of JNK-and p38-dependent signals is required for MET-stimulated proliferation and anchorage-independent growth in MET-transformed fibroblasts and melanoma cells 70,71,72 , and STAT3 signalling and NF-κB activity are necessary for MET-induced onset of leiomyosarcomas and for the survival of prostate cancer cells, respectively 48,76 .…”

Section: Met Signalling In Development and Diseasesupporting

confidence: 87%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,083

1,076

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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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Section: Met Signalling In Development and Diseasesupporting

confidence: 87%

“…2a). Following MET-dependent stimulation, the JNKs and p38s control a range of cellular processes as diverse as cell proliferation, differentiation, transformation and apoptosis 70,71,72,73,74 .…”

mentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,083

1,076

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“…As these four residues are in YXXP motif and are known for the binding of the SH2 domain of Crk (Lamorte et al, 2000), the resulting Gab1 mutant was named as YF-Crk mutant (Figure 3a). The level of Srcinduced phosphorylation of the YF-Crk mutant was 27% of that of the wt Gab1 in HEK293 cells (Figure 3b).…”

Section: C-src Phosphorylates Gab1 On Multiple Tyrosine Residuesmentioning

confidence: 99%

“…Gab1 has six tyrosine residues (Y242, Y259, Y307, Y317, Y373 and Y406) in Tyr-X-X-Pro (YXXP) motifs, which serve as the binding sites for the SH2 domain of the adaptor protein Crk (Lamorte et al, 2000). However, Crk is not the only molecule bound to those residues in YXXP motifs in Gab1.…”

Section: Introductionmentioning

confidence: 99%

Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions

Lai

et al. 2009

Oncogene

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The docking protein Grb2-associated binder1 (Gab1) has a central role in the integration of the growth-factor signaling. In this study, we aimed to examine the significance of Src-mediated Gab1 phosphorylation in the hepatocyte growth factor (HGF) signaling. Using both mutagenesis and mass spectrometry approaches, Y242, Y259, Y317, Y373 and Y627 of Gab1 were identified to be phosphorylated by c-Src. It is interesting to note that the binding of the tyrosine phosphatase SHP2 to the Y627 antagonized the effect of c-Src on the phosphorylation of the other four tyrosine residues. Moreover, the tyrosine residues predominantly phosphorylated by c-Src were different from those predominantly phosphorylated by the HGF receptor. Gab1 overexpression potentiated both mitogenic and motogenic activities of HGF. However, a Gab1 mutant with substitutions of the Src phosphorylation sites (Y242, Y259, Y317 and Y373) failed to promote HGF-induced DNA synthesis, but retained its ability to facilitate HGF-induced chemotaxis. Taken together, our results not only suggest that the phosphorylation of Gab1 by c-Src is important for HGF-induced DNA synthesis, but also provide an example to illustrate how a docking protein (for example, Gab1) is differentially phosphorylated by c-Src and a receptor tyrosine kinase to emanate full spectrum of signals to the downstream.

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“…Gab1 acts to integrate signals downstream from the Met receptor. Following tyrosine phosphorylation, Gab1 associates with multiple signaling proteins including the p85 subunit of PI3K, phospholipase C␥, CrkII/L, and the SHP-2 tyrosine phosphatase (29,(35)(36)(37)(38)(39)(40). The Gab1 PH domain has specificity for phosphatidylinositol 3,4,5-trisphosphate and is required for the morphogenic response downstream from the Met receptor (29,41) as is the recruitment of the SHP-2 phosphatase to Gab1 (39).…”

mentioning

confidence: 99%

Crk Synergizes with Epidermal Growth Factor for Epithelial Invasion and Morphogenesis and Is Required for the Met Morphogenic Program

Lamorte¹,

Rodrigues²,

Naujokas³

et al. 2002

Journal of Biological Chemistry

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Activation of the Met receptor tyrosine kinase through its ligand, hepatocyte growth factor, stimulates cell spreading, cell dispersal, and the inherent morphogenic program of various epithelial cell lines. Although both hepatocyte growth factor and epidermal growth factor (EGF) can activate downstream signaling pathways in Madin-Darby canine kidney epithelial cells, EGF fails to promote the breakdown of cell-cell junctional complexes and initiate an invasive morphogenic program. We have undertaken a strategy to identify signals that synergize with EGF in this process. We provide evidence that the overexpression of the CrkII adapter protein complements EGF-stimulated pathways to induce cell dispersal in two-dimensional cultures and cell invasion and branching morphogenesis in three-dimensional collagen gels. This finding correlates with the ability of CrkII to promote the breakdown of adherens junctions in stable cell lines and the ability of EGF to stimulate enhanced Rac activity in cells overexpressing CrkII. We have previously shown that the Gab1-docking protein is required for branching morphogenesis downstream of the Met receptor. Consistent with a role for CrkII in promoting EGF-dependent branching morphogenesis, the binding of Gab1 to CrkII is required for the branching morphogenic program downstream of Met. Together, our data support a role for the CrkII adapter protein in epithelial invasion and morphogenesis and underscores the importance of considering the synergistic actions of signaling pathways in cancer progression.Epithelial morphogenesis is essential for normal embryonic development and involves proliferation, migration, cellular invasion, turnover of surrounding extracellular matrix, and the deposition of newly synthesized extracellular matrix (1). Several growth factors stimulate the morphogenic program of epithelial cells.

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A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein

Cited by 54 publications

References 51 publications

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

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

Differential phosphorylation of the docking protein Gab1 by c-Src and the hepatocyte growth factor receptor regulates different aspects of cell functions

Crk Synergizes with Epidermal Growth Factor for Epithelial Invasion and Morphogenesis and Is Required for the Met Morphogenic Program

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