Open AccessDocking Protein FRS2 Links the Protein Tyrosine Kinase RET and Its Oncogenic Forms with the Mitogen-Activated Protein Kinase Signaling Cascade
Author(s) -
Rosa Marina Melillo,
Massimo Santoro,
Siew Hwa Ong,
Marc Billaud,
Alfredo Fusco,
Yaron R. Hadari,
Joseph Schlessinger,
Irit Lax
Publication year - 2001
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.21.13.4177-4187.2001
Subject(s) - cancer research , proto oncogene proteins c ret , receptor tyrosine kinase , mitogen activated protein kinase , proto oncogene tyrosine protein kinase src , tyrosine kinase , glial cell line derived neurotrophic factor , biology , tyrosine , signal transduction , microbiology and biotechnology , neurotrophic factors , biochemistry , receptor
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.