Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.
Mol Cell Biol
; 21(13): 4177-87, 2001 Jul.
Article
em En
| MEDLINE
| ID: mdl-11390647
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Proteínas
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Proteínas Proto-Oncogênicas
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Receptores Proteína Tirosina Quinases
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Sistema de Sinalização das MAP Quinases
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Proteínas de Drosophila
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Proteínas Adaptadoras de Transporte Vesicular
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Proteínas Adaptadoras de Transdução de Sinal
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Proteínas de Membrana
Limite:
Humans
Idioma:
En
Revista:
Mol Cell Biol
Ano de publicação:
2001
Tipo de documento:
Article
País de afiliação:
Itália