Phosphatidylinositol 3-kinase Contributes to Erk1/Erk2 MAP Kinase Activation Associated with Hepatocyte Growth Factor-induced Cell Scattering

Sipeki, Szabolcs; Bander, Erzsébet; Buday, László; Farkas, Gyöngyi; Bácsy, E; Ways, D. Kirk; Farago, Anna F.

doi:10.1016/s0898-6568(99)00060-1

Cited by 69 publications

(53 citation statements)

References 23 publications

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“…HepG2 cells have been reported to express c-Met and cell scattering has been reported to be induced by HGF. 22,23 To identify their ganglioside pattern, glycolipids were extracted from HepG2 cells and analyzed by HPTLC. The major gangliosides in the cells were GM3, GM2 and GM1.…”

Section: Expression Of Gangliosides In Hepg2 Cells and Effect Of Gd1amentioning

confidence: 99%

Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met

Hyuga¹,

Kawasaki²,

Hyuga³

et al. 2001

Int. J. Cancer

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We previously reported that ganglioside GD1a, which is highly expressed in poorly metastatic FBJ-S1 cells, inhibits the serum-induced motility of FBJ-LL cells and that the metastatic potential of FBJ-LL cells is completely suppressed by enforced GD1a expression (Hyuga et al., Int J Cancer 1999; 83:685-91). We recently discovered that hepatocyte growth factor (HGF) induces FBJ-LL cell motility. In the present study, the HGF-induced motility of FBJ-S1 cells was found to be one-thirtieth that of FBJ-LL cells. This motility of GD1a-expressing transfectants, which were produced by transfection of FBJ-LL cells with GM2/GD2 synthase cDNA, decreased with increases in their GD1a expression and HGF induced almost no motility in GD1a-pretreated FBJ-LL cells, indicating that GD1a inhibits the HGF-induced motility of GD1a; HGF; motility; scattering Gangliosides are sialylated glycosphingolipids found on the outer layer of the plasma membrane. Changes in ganglioside expression in cancer cells are strongly related to their metastatic potential. 1-5 Although increases in complex ganglioside expression in cancer cells have been considered to be associated with malignancy, in our previous study we found that the poorly metastatic FBJ-S1 cells highly expressed the complex ganglioside GD1a, whereas the highly metastatic FBJ-LL cells only slightly expressed this ganglioside. 6 GD1a inhibited the serum-induced motility of FBJ-LL cells and the metastatic potential of FBJ-LL cells was completely suppressed by enforced GD1a expression. 7 It is possible that GD1a suppresses metastasis of FBJ-LL cells by inhibiting cell migration. The target molecules of GD1a need to be identified to clarify the mechanism of inhibition of metastasis by GD1a. Key words:We recently found that HGF induces FBJ-LL cell motility 8 and that the serum-induced motility of FBJ-LL cells was decreased by treatment of the serum with anti-HGF antibody (unpublished data), suggesting that HGF is a migration-stimulating factor in serum. Since FBJ-LL cells metastasize to the liver and HGF is secreted by nonparenchymal liver cells, HGF may promote liver metastasis of FBJ-LL cells. We suspect that HGF may play a key role in FBJ-LL cell metastasis. HGF is a multipotential modulator of biologic activities in a variety of cell types and it influences the growth, motility, differentiation and morphogenesis of its target cells through the c-Met tyrosine kinase receptor. 9 HGF has been described as a potent chemotactic factor 10 and has been associated with the progression of carcinoma cells. 11 Overexpression of the HGF receptor, c-Met, in malignant cells has been reported in various tissues. 12 Hence HGF may play a crucial role in cancer metastasis.In the present study, we attempted to identify the target molecules of GD1a by analyzing the molecular mechanism of the inhibition of cell migration by GD1a. We found that GD1a inhibited the HGFinduced motility, morphologic change and formation of actin stress fibers in FBJ-LL cells through suppression of tyrosine phosphorylation ...

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Section: Expression Of Gangliosides In Hepg2 Cells and Effect Of Gd1amentioning

confidence: 99%

Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met

Hyuga¹,

Kawasaki²,

Hyuga³

et al. 2001

Int. J. Cancer

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“…1). As a whole, this apparatus leads to efficient activation of downstream signal transduction pathways that include the mitogenactivated protein kinase (MAPK) cascades (extracellular signal-regulated kinase 1 (ERK1) and ERK2, Jun amino-terminal kinases (JNKs) and p38), the phosphoinositide 3-kinase-Akt (PI3K-Akt) axis, signal transducer and activator of transcription proteins (STATs), and the nuclear factor-κB inhibitor-α (IκBα)-nuclear factor-κB (NF-κB) complex 22,25,42,43,44 . All of these pathways positively control MET-dependent cell proliferation, survival and migration.…”

Section: Introductionmentioning

confidence: 99%

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

Trusolino

Bertotti

Comoglio

2010

Nat Rev Mol Cell Biol

1,060

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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“…Binding of HGF to MET [or HGF receptor (HGFR)] results in receptor dimerization and phosphorylation of tyrosine residues, ultimately leading to the phosphorylation of intracellular docking sites where adaptor proteins bind to activate downstream signaling (4,6,7). Activated signaling pathways include mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B), signal transducer and activator of transcription proteins, and nuclear factor-kB (8)(9)(10). In normal physiology, these signaling pathways promote activation of cytoplasmic and nuclear processes, which lead to a variety of cellular functions, including proliferation and protection from apoptosis (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

“…Activated signaling pathways include mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT (protein kinase B), signal transducer and activator of transcription proteins, and nuclear factor-kB (8)(9)(10). In normal physiology, these signaling pathways promote activation of cytoplasmic and nuclear processes, which lead to a variety of cellular functions, including proliferation and protection from apoptosis (8)(9)(10). The MET pathway also mediates functions such as wound healing and hepatic regeneration, and has pivotal roles in normal liver development (11), embryonic placental development, and the formation of muscle and neurons (12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Salgia

2017

Molecular Cancer Therapeutics

130

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MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non-small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or METoverexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555-65.Ó2017 AACR.

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Phosphatidylinositol 3-kinase Contributes to Erk1/Erk2 MAP Kinase Activation Associated with Hepatocyte Growth Factor-induced Cell Scattering

Cited by 69 publications

References 23 publications

Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met

Ganglioside GD1a inhibits HGF-induced motility and scattering of cancer cells through suppression of tyrosine phosphorylation of c-Met

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

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

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