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Molecular and Cellular Biology, July 2001, p. 4177-4187, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4177-4187.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Docking Protein FRS2 Links the Protein Tyrosine Kinase RET and Its Oncogenic Forms with the Mitogen-Activated Protein Kinase Signaling Cascade

R. M. Melillo,1 M. Santoro,1 S.-H. Ong,2 M. Billaud,3 A. Fusco,1 Y. R. Hadari,2 J. Schlessinger,2 and I. Lax2,*

Department of Pharmacology and the Skirball Institute, New York University Medical Center, New York, New York 100162; Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, Naples, Italy1; and Laboratoire de Génétique, CNRS UMR5641, Lyon 69373, France3

Received 12 September 2000/Returned for modification 26 October 2000/Accepted 5 April 2001

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.

* Corresponding author. Mailing address: Department of Pharmacology and the Skirball Institute, New York University Medical Center, 550 First Ave., New York, NY 10016. Phone: (212) 263-2221. Fax: (212) 263-7133. E-mail: laxi01{at}endeavor.med.nyu.edu.

Molecular and Cellular Biology, July 2001, p. 4177-4187, Vol. 21, No. 13
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.13.4177-4187.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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