An alternatively spliced form of Met receptor is tumorigenic

Lee, Jae-Ho; Gao, Chong; Lee, Chong Chou; Kim, Myung Deok; Woude, George F. Vande

doi:10.1038/emm.2006.66

Cited by 45 publications

(46 citation statements)

References 35 publications

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“…However, gain-of-function mutations to c-Met are not exclusive to the tyrosine kinase domain. The juxtamembrane domain is critical for the metabolism of c-Met because mutations in this domain inhibit ubiquitylation, ultimately increasing receptor insertion into the cell membrane (Lee et al, 2006a). The ability of c-Met siRNA treatment of tumor cells to suppress growth and metastasis further highlights the critical role played by c-Met in cancer cell behavior (Corso et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…HGF/c-Met signaling activates several cellular responses, such as proliferation, migration, invasion, and scattering, which are essential for transition to a metastatic phenotype. Many studies have shown that HGF/c-Met activation augments mitogenic and invasive activity in ovarian, glioma, gastric, and lung carcinomas (Ma et al, 2003;Lee et al, 2006a). Elevated c-Met expression and/or activation are generally correlated with a poor prognosis in many malignancies.…”

Section: Discussionmentioning

confidence: 99%

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The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

Yamamoto

Elias²,

Masino³

et al. 2010

J Pharmacol Exp Ther

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The angiotensin (Ang) IV analog norleual [Nle-Tyr-e --(CH 2 -NH 2 )3-4 -His-Pro-Phe] exhibits structural homology with the hinge (linker) region of hepatocyte growth factor (HGF) and is hypothesized to act as a hinge region mimic. Norleual competitively inhibited the binding of HGF to its receptor c-Met in mouse liver membranes, with an IC 50 value of 3 pM. Predictably, norleual was able to inhibit HGF-dependent signaling, proliferation, migration, and invasion in multiple cell types at concentrations in the picomolar range. Ex vivo studies demonstrated that norleual exhibited potent antiangiogenic activity, an attribute that would be predicted for a HGF/c-Met antagonist. Furthermore, norleual suppressed pulmonary colonization by

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

Yamamoto

Elias²,

Masino³

et al. 2010

J Pharmacol Exp Ther

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“…The direct and irreplaceable relationship between Y1003 and Cbl binding was clearly demonstrated when the replacement of Y1003 by a phenylalanine residue abrogated the ubiquitination (15)(16)(17). Thus, in the absence of the JM domain, Cbl is unable to initiate the ubiquitination process of Met and therefore, the receptor remains constitutively active acquiring eventually an oncogenic activity (18,19).…”

Section: Discovery and Oncogenic Potential Of Met Exon 14 Alternativementioning

confidence: 99%

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Pilotto¹,

Gkountakos²,

Carbognin³

et al. 2017

Ann. Transl. Med.

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Abstract:The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

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“…These MET ex14 alterations were shown to promote RNA-splicingbased skipping of MET exon 14, which results in activation of MET kinase activity through a unique mechanism. The portion of the protein encoded by exon 14, most prominently Y1003 in a DpYR motif, is required for effi cient recruitment of the ubiquitin ligase CBL, which targets MET for ubiquitinmediated degradation (16)(17)(18). Loss of MET exon 14 maintains the reading frame and leads to increased MET stability and prolonged signaling upon HGF stimulation, leading to increased oncogenic potential ( 19,20 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

et al. 2015

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Focal amplifi cation and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 ( MET ex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profi les from 38,028 patients to identify 221 cases with MET ex14 mutations (0.6%), including 126 distinct sequence variants. MET ex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring MET ex14 alterations. We also report three new patient cases with MET ex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of MET ex14 mutations indicates that diagnostic testing via comprehensive genomic profi ling is necessary for detection in a clinical setting. SIGNIFICANCE:Here we report the identifi cation of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro . Patients whose tumors harbored these alterations derived meaningful clinical benefi t from MET inhibitors. Collectively, these data support the role of MET ex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefi t from MET inhibitors. Cancer Discov; 5(8);

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An alternatively spliced form of Met receptor is tumorigenic

Abstract: 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).

Cited by 45 publications

References 35 publications

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

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An alternatively spliced form of Met receptor is tumorigenic

Abstract: 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).

Cited by 45 publications

References 35 publications

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH2-NH2)3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH2-NH2)3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors

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Resources

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The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor

The Angiotensin IV Analog Nle-Tyr-Leu-ψ-(CH₂-NH₂)^3-4-His-Pro-Phe (Norleual) Can Act as a Hepatocyte Growth Factor/c-Met Inhibitor