Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis

Day, Regina M.; Cioce, Vittoria; Breckenridge, Diane; Castagnino, Paola; Bottaro, Donald P.

doi:10.1038/sj.onc.1202683

Cited by 78 publications

(121 citation statements)

References 42 publications

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“…ERK/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt are known to be components of major signaling pathways downstream of c-Met/HGF receptor (9,24). Neither doxorubicin-induced cardiomyopathy nor the effects of hHGF gene transfer was found to be related to the activation (phosphorylation) of Akt in the heart 4 wk after doxorubicin treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Esaki

Takemura²,

Kosai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Hepatocyte growth factor (HGF) reportedly exerts beneficial effects on the heart following myocardial infarction and during nonischemic cardiomyopathy, but the precise mechanisms underlying the latter have not been well elucidated. We generated nonischemic cardiomyopathy in mice by injecting them with doxorubicin (15 mg/kg ip). Two weeks later, when cardiac dysfunction was apparent, an adenoviral vector encoding human HGF gene (Ad.CAG-HGF, 1×1011 particles/mouse) was injected into the hindlimb muscles; LacZ gene served as the control. Left ventricular dilatation and dysfunction normally seen 4 wk after doxorubicin administration were significantly mitigated in HGF-treated mice, as were the associated cardiomyocyte atrophy/degeneration and myocardial fibrosis. Myocardial expression of GATA-4 and a sarcomeric protein, myosin heavy chain, was downregulated by doxorubicin, but the expression of both was restored by HGF treatment. The protective effect of HGF against doxorubicin-induced cardiomyocyte atrophy was confirmed in an in vitro experiment, which also showed that neither cardiomyocyte apoptosis nor proliferation plays significant roles in the present model. Upregulation of c-Met/HGF receptor was noted in HGF-treated hearts. Among the mediators downstream of c-Met, the activation of extracellular signal-regulated kinase (ERK) was reduced by doxorubicin, but the activity was restored by HGF. Levels of transforming growth factor-β1 and cyclooxygenase-2 did not differ between the groups. Our findings suggest the HGF gene delivery exerts therapeutic antiatrophic/degenerative and antifibrotic effects on myocardium in cases of established cardiac dysfunction caused by doxorubicin. These beneficial effects appear to be related to HGF-induced ERK activation and upregulation of c-Met, GATA-4, and sarcomeric proteins.

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Section: Resultsmentioning

confidence: 99%

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Esaki

Takemura²,

Kosai³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Activation of the PI3K/PKB pathway by HGF involves recruitment of PI3K to the docking site of Met either by a direct interaction or indirectly via the docking protein GAB1. [43][44][45] Studies in a variety of other cell types have also revealed a prominent regulatory role for PI3K in either HGF-induced proliferation [46][47][48] or survival. [49][50][51] Furthermore, in MM, PI3K has been implicated in IL6-induced proliferation 29,52 and in the rescue from apoptosis by either IL6 29,53 or IGF1.…”

Section: Discussionmentioning

confidence: 99%

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

et al. 2003

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The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/ scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para-or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and antiapoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.

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“…Interestingly, some of the features of EMT such as cell motility may overlap with PI3K-dependent cell scattering induced by HGF (Royal and Park, 1995;Day et al, 1999). In contrast, in a model of multistep carcinogenesis in which TGF-b cooperates with active oncogenic Ras to induce EMT, PI3K protects cells from TGF-b-activated programmed cell death, but is not required for EMT (Janda et al, 2002a).…”

Section: Tgf-b and Pi3kmentioning

confidence: 99%

TGF-β and epithelial-to-mesenchymal transitions

2005

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Remarkable phenotype plasticity of epithelial cells underlies morphogenesis, epithelial repair and tumor invasiveness. Detailed understanding of the contextual cues and molecular mediators that control epithelial plasticity will be required in order to develop viable therapeutic approaches targeting epithelial-to-mesenchymal transition (EMT), an advanced manifestation of epithelial plasticity. Members of the transforming growth factor (TGF-b) family of growth factors can initiate and maintain EMT in a variety of biological systems and pathophysiological context by activating major signaling pathways and transcriptional regulators integrated in extensive signaling networks. Here we will review the distinct physiological contexts of EMT and the underlying molecular signaling networks controlled by TGF-b.

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Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis

Cited by 78 publications

References 42 publications

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

Treatment with an adenoviral vector encoding hepatocyte growth factor mitigates established cardiac dysfunction in doxorubicin-induced cardiomyopathy

The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma

TGF-β and epithelial-to-mesenchymal transitions

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