Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

Woolf, Adrian S.; Kolatsi-Joannou, Maria; Hardman, Patricia; Andermarcher, E.; Moorby, Catriona D.; Fine, Leon G.; Jat, Parmjit; Noble, Mark; Gherardi, Ermanno

doi:10.1083/jcb.128.1.171

Cited by 300 publications

(163 citation statements)

References 52 publications

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“…Two of these lines also showed an increased mitogenic response to exogenous HGF/SF Furthermore, transfection of human Met and HGF/SF genes into 3T3 cells results in cell lines highly tumorigenic in nude mice, as a result of autocrine stimulatory mechanisms (Rong et al, 1992). Mesangial fibroblasts also both secrete HGF/SF and synthesize Met (Kolatsi-Joannou et al, 1995). The addition of HGF/SF causes an increase in the bipolar morphology of mesangial cells, suggesting an autocrine role of HGF/SF in maintaining fibroblast morphology.…”

Section: Discussionmentioning

confidence: 99%

“…HGF/SF acts via a paracrine mechanism of action. More generally, in early development, coexpression of the HGF/SF and c-Met genes precedes separate expression in adjacent tissues, which occurs as organogenesis proceeds (Sonnenberg et al, 1993;Woolf et al, 1995;Andermacher et al, 1996). Therefore the sarcomatoid mesothelioma cell lines may reflect a more primitive mesenchymal developmental state.…”

Section: Discussionmentioning

confidence: 99%

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Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology

Harvey

Warn²,

Dobbin³

et al. 1998

Br J Cancer

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Summary The expression of hepatocyte growth factor/scatter factor (HGF/SF) was studied in 12 BR became more elongated and bipolar, while BT formed more spread-out cell colonies. HGF/SF acted as a paracrine effector on the epithelioid BT cells and stimulated both cell-spreading and proliferation. Interestingly, BT cells spread but did not scatter in response to exogenous HGF/SF. In contrast BR cells showed only some stimulation of cell motility with HGF/SF and no increase in cell proliferation was observed. Because HGF/SF was previously found in the pleural effusion fluids of patients with malignant mesothelioma and in paraffinembedded tumour tissues, it is concluded that HGF/SF may well stimulate the growth and spread of malignant mesothelioma in vivo by paracrine and/or autocrine mechanisms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology

Harvey

Warn²,

Dobbin³

et al. 1998

Br J Cancer

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“…The degree of increase observed in both cell growth (155% increase compared with untreated controls) and candidate gene mRNA levels after HGF/SF exposure are entirely consistent with the highly differentiated, untransformed nature of the PTECs used which, unlike many tumour cell lines, do not display large changes in their growth rate after growth factor exposure. Furthermore, in view of the powerful mitogenic and morphogenic effects of HGF/SF on PTECs (Cantly et al, 1994;Woolf et al, 1995), studies in which the observed changes in gene expression are related to cell cycle, proliferative and morphogenic parameters would be of further interest.…”

Section: Discussionmentioning

confidence: 99%

“…Serum levels of HGF/SF are rapidly induced after renal injury or failure (Chang et al, 1996). HGF/SF is also believed to have a role in normal renal development and is the most potent renal tubular cell mitogen identified so far (Harris et al, 1993;Cantley et al, 1994;Woolf et al, 1995). Precise details of how HGF/SF promotes renal tubular cell mitogenesis are not known, although HGF/SF stimulation has been reported to increase in vivo expression of the VEGF gene in non-renal systems (Silvagno et al, 1995).…”

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confidence: 99%

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

Clifford

Czapla²,

Richards³

et al. 1998

Br J Cancer

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Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway. Images Figure 1

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“…Signaling via this receptorligand pair has been shown to affect a wide range of biological activities, including cell scattering and growth, morphogenic differentiation, angiogenesis, and mesenchymal to epithelial conversion (3,5,16,18,19,25,29,44,56,57). HGF/SF-Met signaling in vivo has been shown to be essential for normal embryological development (1,48,58) and is believed to play a role in tissue regeneration and wound healing, as well as in the development of the nervous system, kidney, muscle, mammary gland, and liver (1,25,26,35,47,48,50,54,63,65). While HGF/SF-Met signaling clearly mediates a variety of normal cellular processes, this receptor-ligand pair has also been implicated in the generation and spread of tumors (22).…”

mentioning

confidence: 99%

Degradation of the Met Tyrosine Kinase Receptor by the Ubiquitin-Proteasome Pathway

Jeffers

Taylor

Weidner

et al. 1997

Molecular and Cellular Biology

214

182

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The Met tyrosine kinase receptor is a widely expressed molecule which mediates pleiotropic cellular responses following activation by its ligand, hepatocyte growth factor/scatter factor (HGF/SF). In this communication we demonstrate that significant Met degradation is induced by HGF/SF and that this degradation can be blocked by lactacystin, an inhibitor of proteasome activity. We also show that Met is rapidly polyubiquitinated in response to ligand and that polyubiquitinated Met molecules, which are normally unstable, are stabilized by lactacystin. Both HGF/SF-induced degradation and polyubiquitination of Met were shown to be dependent on the receptor possessing intact tyrosine kinase activity. Finally, we found that a normally highly labile 55-kDa fragment of the Met receptor is stabilized by lactacystin and demonstrate that it represents a cell-associated remnant that is generated following the ligand-independent proteolytic cleavage of the Met receptor in its extracellular domain. This truncated Met molecule encompasses the kinase domain of the receptor and is itself tyrosine phosphorylated. We conclude that the ubiquitin-proteasome pathway plays a significant role in the degradation of the Met tyrosine kinase receptor as directed by ligand-dependent and -independent signals. We propose that this proteolytic pathway may be important for averting cellular transformation by desensitizing Met signaling following ligand stimulation and by eliminating potentially oncogenic fragments generated via extracellular cleavage of the Met receptor.

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Roles of hepatocyte growth factor/scatter factor and the met receptor in the early development of the metanephros.

Cited by 300 publications

References 52 publications

Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology

Expression of HGF/SF in mesothelioma cell lines and its effects on cell motility, proliferation and morphology

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes

Degradation of the Met Tyrosine Kinase Receptor by the Ubiquitin-Proteasome Pathway

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