Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. (Articolo in rivista)

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  • Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. (Articolo in rivista) (literal)
Anno
  • 2001-01-01T00:00:00+01:00 (literal)
Alternative label
  • Melillo R.M. 2, Santoro M. 2, Ong S.H. 1, Billaud M. 3, Fusco A. 2, Hadari Y.R. 1, Schlessinger J. 1, Lax I. 1 (2001)
    Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.
    in Molecular and cellular biology (Print)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Melillo R.M. 2, Santoro M. 2, Ong S.H. 1, Billaud M. 3, Fusco A. 2, Hadari Y.R. 1, Schlessinger J. 1, Lax I. 1 (literal)
Pagina inizio
  • 4177 (literal)
Pagina fine
  • 4187 (literal)
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  • Impact Factor = 9,866 Interdisciplinarietà del prodotto: The Authors belong to different scientific areas, sectors and Istitutions. The paper was in collaboration with International Institutions. (literal)
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  • 21 (literal)
Rivista
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  • The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for \"glial cell-derived neurotrophic factors\") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas. (literal)
Note
  • ISI Web of Science (WOS) (literal)
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  • 1 Department of Pharmacology and the Skirball Institute, New York University Medical Center, New York USA; 2 Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy; 3 Laboratoire de Génétique, CNRS UMR5641, Lyon, France (literal)
Titolo
  • Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade. (literal)
Abstract
  • The receptor tyrosine kinase RET functions as the signal transducing receptor for the GDNF (for \"glial cell-derived neurotrophic factors\") family of ligands. Mutations in the RET gene were implicated in Hirschsprung disease (HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine phosphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by binding of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activation by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation of FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-function HSCR-associated RET mutants exhibit impaired FRS2 binding and reduced MAP kinase activation. These experiments demonstrate that FRS2 couples both ligand-regulated and oncogenic forms of RET, with the MAP kinase signaling cascade as part of the response of RET under normal biological conditions and pathological conditions, such as MEN 2 and papillary thyroid carcinomas. (literal)
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