GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Uncoupling signal transducers from oncogenic MET mutants abrogates cell transformation and inhibits invasive growth
    Proceedings of the National Academy of Sciences ; 1998
    In:  Proceedings of the National Academy of Sciences Vol. 95, No. 24 ( 1998-11-24), p. 14379-14383
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 95, No. 24 ( 1998-11-24), p. 14379-14383
    Abstract: The assumption that genes encoding tyrosine kinase receptors could play a role in human cancers has been confirmed by the identification of oncogenic mutations in the kinase domain of RET and KIT . Recently, homologous residues were found mutated in MET , in papillary renal carcinomas (PRCs). The link coupling these genetic lesions to cellular transformation is still unclear. MET PRC mutations result in increased kinase activity and—in some instances, i.e., M1250T substitution—in changes in substrate specificity. A direct correlation occurs between the transforming potential of MET PRC mutants and their ability to constitutively associate with signal transducers through two phosphorylated tyrosines (Y 1349 VHVNATY 1356 VNV) located in the receptor tail. Substitution of these “docking tyrosines” with phenylalanines leaves unaffected the altered properties of the kinase but abrogates transformation and invasiveness in vitro . Uncoupling the receptor from signal transducers with a tyrosine-phosphorylated peptide derivative (Y p VNV) inhibits invasive growth induced by MET PRC mutants. These data indicate that constitutive receptor coupling to downstream signal transducers is a key mechanism in neoplastic transformation driven by mutated MET and suggest a therapeutic strategy to target neoplastic diseases associated with this oncogene.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.95.24.14379
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1998
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity
    Proceedings of the National Academy of Sciences ; 2006
    In:  Proceedings of the National Academy of Sciences Vol. 103, No. 13 ( 2006-03-28), p. 5090-5095
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 13 ( 2006-03-28), p. 5090-5095
    Abstract: Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs’ biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro , chronic treatment of carcinoma cell lines resulted in impairment of HGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo , administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nu / nu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: ( i ) cleavage of the extracellular portion, resulting in “shedding” of the ectodomain, and ( ii ) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the “decoy effect” generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0508156103
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2006
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    A point mutation in the MET oncogene abrogates metastasis without affecting transformation
    Proceedings of the National Academy of Sciences ; 1997
    In:  Proceedings of the National Academy of Sciences Vol. 94, No. 25 ( 1997-12-09), p. 13868-13872
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 94, No. 25 ( 1997-12-09), p. 13868-13872
    Abstract: The MET oncogene encodes the tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF), known to stimulate invasive growth of epithelial cells. MET is overexpressed in a significant percentage of human cancers and is amplified during the transition between primary tumors and metastasis. To investigate whether this oncogene is directly responsible for the acquisition of the metastatic phenotype, we exploited a single-hit oncogenic version of MET , able to transform and to confer invasive and metastatic properties to nontumorigenic cells, both in vitro and in nude mice. We mutagenized the signal transducer docking site of Met (Y 1349 VHVX 3 Y 1356 VNV), which has the uncommon property of binding and activating multiple src homology region 2 (SH2)-containing intracellular effectors. Notably, a point mutation (H 1351 → N) increased the transforming ability of the oncogene but abolished its metastatic potential. This mutation duplicates the Grb2 binding site, super-activating the Ras pathway and preventing the binding of the other intracellular transducers. Complementation in trans with another nonmetastatic mutant (N 1358 → H), recruiting all the transducers downstream to Met except Grb2, rescued the invasive–metastatic phenotype. It is concluded that the metastatic potential of the MET oncogene relies on the properties of its multifunctional docking site, and that a single point mutation affecting signal transduction can dissociate neoplastic transformation from metastasis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.94.25.13868
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 1997
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Wild-type p53 controls cell motility and invasion by dual regulation of MET expression
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 34 ( 2011-08-23), p. 14240-14245
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 34 ( 2011-08-23), p. 14240-14245
    Abstract: Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: ( i ) transactivation of MET-targeting miR-34 , and ( ii ) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1017536108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Reviving oncogenic addiction to MET bypassed by BRAF (G469A) mutation
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 40 ( 2018-10-02), p. 10058-10063
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 40 ( 2018-10-02), p. 10058-10063
    Abstract: Cancer clonal evolution is based on accrual of driving genetic alterations that are expected to cooperate and progressively increase malignancy. Little is known on whether any genetic alteration can hinder the oncogenic function of a coexisting alteration, so that therapeutic targeting of the one can, paradoxically, revive the function of the other. We report the case of a driver oncogene (MET) that is not only bypassed, but also disabled by the mutation of a downstream transducer (BRAF), and reignited by inhibition of the latter. In a metastasis originated from a cancer of unknown primary (CUP), the MET oncogene was amplified eightfold, but unexpectedly, the kinase was dephosphorylated and inactive. As result, specific drugs targeting MET (JNJ-38877605) failed to inhibit growth of xenografts derived from the patient. In addition to MET amplification, the patient harbored, as sole proliferative driver, a mutation hyperactivating BRAF (G469A). Surprisingly, specific blockade of the BRAF pathway was equally ineffective, and it was accompanied by rephosphorylation of the amplified MET oncoprotein and by revived addiction to MET. Mechanistically, MET inactivation in the context of the BRAF-activating mutation is driven through a negative feedback loop involving inactivation of PP2A phosphatase, which in turn leads to phosphorylation on MET inhibitory Ser985. Disruption of this feedback loop allows PP2A reactivation, removing the inhibitory phosphorylation from Ser985 and thereby unleashing MET kinase activity. Evidence is provided for a mechanism of therapeutic resistance to single-oncoprotein targeting, based on reactivation of a genetic alteration functionally dormant in targeted cancer cells.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1721147115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...