Two North American Families With Hereditary Papillary Renal Carcinoma and Identical Novel Mutations in the MET Proto-Oncogene

Schmidt, Laura S.; Junker, Kerstin; Weirich, Gregor; Glenn, Gladys; Choyke, Peter L.; Lubensky, Irina A.; Zhuang, Zhengping; Jeffers, Michael; G, Vande Woude; Neumann, Hartmut P. H.; Walther, McClellan M.; Wm, Linehan; Zbar, B.

doi:10.1097/00005392-199905000-00137

Cited by 86 publications

(62 citation statements)

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“…It is also possible that conformational changes of tyrosine kinase domains and the activation loop may cause destabilization of the activation loop. In a series of sequence analyses reported previously, all activating mutations were located in the kinase domain (Park et al, 1999;Schmidt et al, 1997Schmidt et al, , 1998Schmidt et al, , 1999. Almost all mutations were close to the entrance of the adenine-binding pocket or in the activation loop (Schmidt et al, 1999).…”

Section: Discussionmentioning

confidence: 89%

“…Their transformed phenotype, renal carcinoma cells, also express HGFR (Nakopoulou et al, 1997;Natali et al, 1996). Recent studies have demonstrated germline or somatic mutations of HGFR in hereditary and sporadic renal cell carcinomas and childhood hepatocellular carcinomas (Park et al, 1999;Schmidt et al, 1997Schmidt et al, , 1998Schmidt et al, , 1999. Many of these mutations have been shown to increase the basal kinase activity of HGFR, so-called constitutive activation, and expression of these mutated receptors was found to be associated with their transforming potential of normal ®broblasts (Jeers et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

et al. 2001

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Dysregulated cell motility is one of the major characteristics of invasion and metastatic potentials of malignant tumor cells. Here, we examined the hepatocyte growth factor (HGF)-induced cell motility of two human renal carcinoma cell lines, ACHN and VMRC-RCW. Scattering and migration was induced in ACHN in an HGFdependent manner, whereas they were maintained in VMRC-RCW even in the absence of HGF. In VMRC-RCW, HGF receptor (HGFR) tyrosine kinase was constitutively active, and sequence analysis showed N375S, A1209G and V1290L mutations. However, transfection experiments using porcine aortic endothelial (PAE) cells demonstrated that no single mutation or combination of two or three mutations caused HGFindependent constitutive activation. Conversely, the expressed amount of receptor protein had a pivotal role in the basal kinase activity. With respect to downstream signaling molecules of HGFR in ACHN or VMRC-RCW, the Ras-MAPK pathway was downregulated, whereas phosphoinositide 3-kinase (PI3-kinase) was not further activated by HGF-treatment in VMRC-RCW cells. The PI3-kinase inhibitors, wortmannin and LY294002 strongly inhibited spontaneous migration of VMRC-RCW. One transfected PAE cell line with massive overexpression of HGFR demonstrated scattered morphology and increased PI3-kinase activity in association with increased motility, which was partially inhibited by LY294002. Taken together, our results indicate that the overexpression of HGFR causes increase in cellular motility and PI3-kinase shows the important contribution on the increased motility of renal carcinoma cells. Oncogene (2001) 20, 7610 ± 7623.

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Section: Discussionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

et al. 2001

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“…Mutations in the remaining samples were previously reported in Schmidt et al, 1997Schmidt et al, , 1998 points of the structure to facilitate subdomain movement. Molecular modeling studies described here suggest this type of activating mechanism for MET mutations in papillary renal carcinoma.…”

Section: Discussionmentioning

confidence: 96%

Novel mutations of the MET proto-oncogene in papillary renal carcinomas

et al. 1999

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Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET protooncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected ®ve novel missense mutations; three of ®ve mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a dierent mechanism than hereditary papillary renal carcinoma.

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“…In MET-speci®c RT ± PCR products, we sequenced the kinase domain, where germline and somatic mutations found in papillary renal carcinomas have been previously located (Schmidt et al, , 1998Fischer et al, 1998;Olivero et al, 1999). We identi®ed MET gene somatic mutations in ten lymph node metastases (out of the 46 MET-positive metastases) harvested from 4/15 HNSCC cases studied.…”

Section: Identification Of Met Gene Mutations In Hnscc Metastasesmentioning

confidence: 99%

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas

et al. 2000

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A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identi®ed. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identi®ed two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis. Oncogene (2000) 19, 1547 ± 1555.

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Two North American Families With Hereditary Papillary Renal Carcinoma and Identical Novel Mutations in the MET Proto-Oncogene

Cited by 86 publications

References 0 publications

Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

Increase in hepatocyte growth factor receptor tyrosine kinase activity in renal carcinoma cells is associated with increased motility partly through phosphoinositide 3-kinase activation

Novel mutations of the MET proto-oncogene in papillary renal carcinomas

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas

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