Frequency ofTPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives

Yu, Jun; Miehlke, Stephan; Ebert, Matthias P.; Hoffmann, Juliane; Breidert, Matthias; Alpen, Birgit; Starzyńska, Teresa; Prof., Manfred Stolte; Prof., Peter Malfertheiner; Prof., Ekkehard Bayerdörffer

doi:10.1002/(sici)1097-0142(20000415)88:8<1801::aid-cncr7>3.0.co;2-u

Cited by 64 publications

(31 citation statements)

References 23 publications

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“…In the hybrid Tpr-Met protein, Tpr sequences replace the extracellular domain of the receptor, causing constitutive dimerization of the kinase domain (Rodrigues and Park 1993). This form of activation is rarely found in human cancers (Soman et al, 1991;Yu et al, 2000). The Met receptor is more frequently activated in carcinomas and sarcomas by overexpression, or by the presence of an ectopic HGF loop (Rong et al, 1993;Cortner et al, 1995).…”

Section: Introductionsupporting

confidence: 88%

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K252a inhibits the oncogenic properties of Met, the HGF receptor

et al. 2002

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The ATP analog K252a is a potent inhibitor for receptor tyrosine kinases of the Trk family. Here we show that nanomolar concentrations of K252a prevent HGFmediated scattering in MLP-29 cells (30 nM), reduce Met-driven proliferation in GTL-16 gastric carcinoma cells (100 nM), and cause reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, TprMet (75 nM). K252a inhibits Met autophosphorylation in cultured cells and in immunoprecipitates and prevents activation of its downstream effectors MAPKinase and Akt. Interestingly, K252a seems to be more effective at inhibiting the mutated form of Met (M1268T) found in papillary carcinoma of the kidney than the wild type receptor. Pretreatment of both Tpr-Met-transformed NIH3T3 fibroblasts and of GTL-16 gastric carcinoma cells with K252a results in loss of their ability to form lung metastases in nude mice upon injection into the caudal vein. These observations suggest that K252a derivatives, which are active in vivo as anti-cancer drugs in models of Trk-driven malignancies, should also be effective for treatment of Met-mediated tumors.

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Section: Introductionsupporting

confidence: 88%

“…This rearrangement has recently been found in some patients with gastric cancer (Soman et al, 1991;Yu et al, 2000). Tpr-Met is highly transforming in NIH3T3 fibroblasts.…”

Section: K252a Reverts the Phenotype Of Nih3t3 Cells Transformed By Tmentioning

confidence: 99%

K252a inhibits the oncogenic properties of Met, the HGF receptor

et al. 2002

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“…Tpr-Met has been found in some cases of gastric cancers as well as in precursor lesions and in the adjacent healthy gastric mucosa. 19,20 This suggests that Tpr-Met may be involved at an early stage of tumorigenesis and remain necessary for gastric tumor maintenance. Thus, Tpr-Met-directed silencing strategies may have therapeutic value.…”

Section: Discussionmentioning

confidence: 99%

“…18 Although not common in human tumors, Tpr-Met has been reported in gastric carcinomas. 19,20 This suggests that MNNG or related carcinogens, present in trace amounts in food, Met can also be activated by mutation or overexpression. Numerous activating point mutations were discovered in the kinase domain of Met in all hereditary and most sporadic cases of papillary renal carcinoma, as well as in some cases of childhood hepatocellular carcinoma and of metastatic head and neck squamous cell carcinoma.…”

mentioning

confidence: 99%

RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis

et al. 2005

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Tpr-Met, the oncogenic counterpart of the Met receptor, has been detected in gastric cancers, as well as in precursor lesions and in the adjacent normal gastric mucosa. This has prompted the suggestion that Tpr-Met may predispose to the development of gastric tumors. Given the sequence specificity of RNA interference, oncogenes activated by point mutation or rearrangements can be targeted while spearing the product of the wild-type allele. In this work, we report specific suppression of Tpr-Met expression and inhibition of Tpr-Met-mediated transformation and tumorigenesis by means of a short interfering RNA (siRNA) directed toward the Tpr-Met junction (anti-TM2). When delivered by a lentiviral vector, anti-TM2 siRNA was effective also in mouse embryonal fibroblasts or epithelial cells expressing high levels of Tpr-Met. Our results suggest that lentiviral-mediated delivery of anti-TM2 siRNA may be developed into a powerful tool to treat Tpr-Met-positive cancers.

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“…TPR-Met arises from chromosomal fusion of the translocated promoter region (TPR) in chromosome 1 with the Met carboxyl-terminal sequence on chromosome 7 (22,23). This rearrangement has been observed in patients with gastric carcinoma (24). A large body of evidence demonstrates that misregulation of the Met signaling pathway is involved in many types of human cancers.…”

mentioning

confidence: 99%

Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

Xia

Baker

et al. 2011

Journal of Biological Chemistry

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Protein tyrosine phosphorylation is a ubiquitous, fundamental biochemical mechanism that regulates essential eukaryotic cellular functions. The level of tyrosine phosphorylation of specific proteins is finely tuned by the dynamic balance between protein tyrosine kinase and protein tyrosine phosphatase activities. Hepatocyte growth factor receptor (also known as Met), a receptor protein tyrosine kinase, is a major regulator of proliferation, migration, and survival for many epithelial cell types. We report here that receptor-type protein tyrosine phosphatase ␤ Hepatocyte growth factor (HGF)3 , also known as scatter factor, is expressed in numerous tissues (1-5) and participates in the regulation of angiogenesis, organogenesis, tissue repair, and neural induction (6). HGF induces random movement/scattering in epithelial cells as well as dissociation, migration, and invasion of cells through the extracellular matrix in vivo (7,8). HGF is mitogenic in many normal cell types, including epithelial cells, vascular endothelial cells, and melanocytes. HGF is also a morphogen that induces transition of epithelial cells into a mesenchymal morphology and formation of branched tubelike structures (9, 10). In keratinocytes, HGF has been shown to promote motility and proliferation (11,12). Each of these biological effects exerted by HGF is triggered by stimulation of its cell surface receptor, Met (also known as HGF receptor), with concomitant activation of downstream effecter molecules (8,13,14).Upon ligand binding, Met autophosphorylates several tyrosine residues in its carboxyl-terminal domain. Met function is controlled by its state of tyrosine phosphorylation (15-17). Among the tyrosines within the carboxyl terminus, phosphorylation of tyrosines 1234 and 1235, located within the catalytic domain, is required for tyrosine kinase activity (15-17). Phosphorylation of tyrosines 1349 and 1356, which are highly conserved among other members of the Met family, such as Sea and Ron, are necessary for most biological activities of . Tyrosines 1349 and 1356, when phosphorylated, serve as multifunctional binding sites for Gab1, Grab2, PI3K, phospholipase C-␥, SHP2, and Cbl proto-oncogene. Phosphorylation of tyrosine 1356 is essential for transducing signals for cell motility and morphogenesis (19 -21).In addition to its roles in many normal physiological processes, Met also plays important roles in human malignancy. Met was originally identified as the TPR-Met oncogene, which possesses ligand-independent tyrosine kinase activity. TPR-Met arises from chromosomal fusion of the translocated promoter region (TPR) in chromosome 1 with the Met carboxyl-terminal sequence on chromosome 7 (22, 23). This rearrangement has been observed in patients with gastric carcinoma (24). A large body of evidence demonstrates that misregulation of the Met signaling pathway is involved in many types of human cancers. Inappropriate expression of HGF/Met autocrine signaling confers increased tumorigenesis and metastatic activity in vivo, and Met expression o...

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Frequency ofTPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives

Cited by 64 publications

References 23 publications

K252a inhibits the oncogenic properties of Met, the HGF receptor

K252a inhibits the oncogenic properties of Met, the HGF receptor

RNAi technology and lentiviral delivery as a powerful tool to suppress Tpr-Met-mediated tumorigenesis

Receptor-type Protein Tyrosine Phosphatase β (RPTP-β) Directly Dephosphorylates and Regulates Hepatocyte Growth Factor Receptor (HGFR/Met) Function

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