Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

Vigna, Elisa; Gramaglia, Daniela; Longati, Paola; Bardelli, Alberto; Comoglio, Paolo M.

doi:10.1038/sj.onc.1202791

Cited by 64 publications

(57 citation statements)

References 33 publications

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“…It was reported that the addition of the juxtamembrane domain to TPR-Met fusion protein abolished the transforming activity of TPR-Met (Vigna et al, 1999), suggesting this domain has inhibitory effect on the transforming activity of activated Met. Actually, the part of juxtamembrane domain deleted in Met-SM was believed to act as regulatory sites of the enzymatic activity of Met.…”

Section: Discussionmentioning

confidence: 99%

An alternatively spliced form of Met receptor is tumorigenic

Lee

Gao²,

Lee³

et al. 2006

Exp Mol Med

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Section: Discussionmentioning

confidence: 99%

An alternatively spliced form of Met receptor is tumorigenic

Lee

Gao²,

Lee³

et al. 2006

Exp Mol Med

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“…The juxtamembrane domain of c-Met has been considered to play a negative regulatory function, based on findings that addition of the juxtamembrane domain to oncogenic TPR-Met fusion protein abolishes its transforming activity (25), and phosphorylation of Tyr-1003 in this domain facilitates proteasome-mediated degradation of c-Met through Cbl association (26). Furthermore, mutations in the juxtamembrane domain were identified in human gastric cancer and small cell lung cancer, and these mutant c-Met are more susceptible to tyrosine phosphorylation upon HGF stimulus (27,28), again indicating that the domain contributes to negative regulation of c-Met.…”

Section: Inhibition Of Cellularmentioning

confidence: 99%

Bi-directional Regulation of Ser-985 Phosphorylation of c-Met via Protein Kinase C and Protein Phosphatase 2A Involves c-Met Activation and Cellular Responsiveness to Hepatocyte Growth Factor

Hashigasako

Machide

Nakamura

et al. 2004

Journal of Biological Chemistry

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Hepatocyte growth factor (HGF), 1 originally identified and cloned as a mitogenic protein for hepatocytes (1-3), evokes multiple cellular responses, including mitogenesis, morphogenesis, migration, and anti-apoptosis (4 -6). These biological activities of HGF are triggered by tyrosine phosphorylation of c-Met, a specific receptor tyrosine kinase for HGF (7). Biological activities of HGF support tissue organization during development and regeneration of organs, including the liver, kidney, placenta, and skeletal muscle (4 -6), but unregulated and/or constitutive activation of the c-Met receptor endows tumor cells with invasive and metastatic characteristics (8, 9).The c-Met receptor is a heterodimeric protein composed of extracellular ␣-chain and membrane-spanning ␤-chain, which contains an intracellular tyrosine kinase domain. Specific binding of HGF to the c-Met receptor activates tyrosine kinase activity, thereby facilitating phosphorylation of C-terminal tyrosine residues, so-called multifunctional docking sites (10, 11). In addition to the catalytic tyrosine kinase domain, the ␤-chain contains a juxtamembrane domain of 47 amino acid residues, which is highly conserved in distinct species (12). Previous studies indicated that a serine residue at position 985, which resides in the juxtamembrane domain of c-Met, is phosphorylated by treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator for protein kinase C (PKC). Most interesting, Ser-985 phosphorylation was associated with decreased tyrosine phosphorylation of the c-Met receptor (13); however, neither regulatory mechanisms nor the biological significance of the Ser-985 phosphorylation of c-Met has been elucidated.In the present study, we found that the phosphorylation status of juxtamembrane Ser-985 of the c-Met receptor is bidirectionally regulated through reverse activities of PKC␦/⑀ and protein phosphatase 2A (PP2A), a serine/threonine protein phosphatase. Likewise, oxidative stress in cells induced PKCmediated Ser-985 phosphorylation, and this was associated with inhibition of c-Met tyrosine phosphorylation and subsequent biological responses upon HGF stimulus. Our observations mean that the Ser-985 phosphorylation of c-Met mediated via PKCs and PP2A provides a unique mechanism, which confers cellular responsiveness/unresponsiveness to HGF, depending on the extracellular environment and conditions.

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“…7 In contrast to the positive signaling triggered by the C-terminal tail, the juxtamembrane region is endowed with several negative regulatory sites, which are involved in recycling and/or degradation of the receptor. [8][9][10][11][12] The ligand-activated MET stimulates proliferation, scattering, invasion and morphogenesis of epithelial cells, acts as an angiogenic factor and has chemoattractant and neurotrophic activities. HGF/SF is also a survival factor, which protects a number of cell types against cell toxicity and apoptosis.…”

mentioning

confidence: 99%

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

et al. 2006

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Activation of the MET tyrosine kinase receptor by hepatocyte growth factor/scatter factor is classically associated with cell survival. Nonetheless, stress stimuli can lead to a caspase-dependent cleavage of MET within its juxtamembrane region, which generate a proapoptotic 40 kDa fragment (p40 MET). We report here that p40 MET is in fact generated through an additional caspase cleavage of MET within its extreme C-terminal region, which removes only few amino acids. We evidenced a hierarchical organization of these cleavages, with the C-terminal cleavage favoring the juxtamembrane one. As a functional consequence, the removal of the last amino acids of p40 MET increases its apoptotic capacity. Finally, cells expressing a MET receptor mutated at the C-terminal caspase site are unable to generate p40 MET and are resistant to apoptosis, indicating that generation of p40 MET amplifies apoptosis. These results revealed a two-step caspase cleavage of MET resulting in the reshaping of this survival receptor to a proapoptotic factor.

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Loss of the exon encoding the juxtamembrane domain is essential for the oncogenic activation of TPR-MET

Cited by 64 publications

References 33 publications

An alternatively spliced form of Met receptor is tumorigenic

An alternatively spliced form of Met receptor is tumorigenic

Bi-directional Regulation of Ser-985 Phosphorylation of c-Met via Protein Kinase C and Protein Phosphatase 2A Involves c-Met Activation and Cellular Responsiveness to Hepatocyte Growth Factor

Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

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