FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

doi:10.1128/MCB.20.3.979-989.2000

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Molecular and Cellular Biology, February 2000, p. 979-989, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

FRS2 Proteins Recruit Intracellular Signaling Pathways by Binding to Diverse Targets on Fibroblast Growth Factor and Nerve Growth Factor Receptors

S. H. Ong,¹ G. R. Guy,¹ Y. R. Hadari,² S. Laks,² N. Gotoh,² J. Schlessinger,² and I. Lax²^,^*

Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore 117609, Singapore¹ and Department of Pharmacology and the Skirball Institute, New York University School of Medicine, New York, New York 10016²

Received 14 May 1999/Returned for modification 30 June 1999/Accepted 29 October 1999

The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF)or nerve growth factor (NGF) receptors to the Ras/mitogen-activatedprotein kinase signaling cascade. The two members of the FRS2family, FRS2 $alpha$ and FRS2 $beta$ , are structurally very similar. Each iscomposed of an N-terminal myristylation signal, a phosphotyrosine-binding(PTB) domain, and a C-terminal tail containing multiple bindingsites for the SH2 domains of the adapter protein Grb2 and theprotein tyrosine phosphatase Shp2. Here we show that the PTB domainsof both the $alpha$ and $beta$ isoforms of FRS2 bind directly to the FGFor NGF receptors. The PTB domains of the FRS2 proteins bind toa highly conserved sequence in the juxtamembrane region of FGFR1.While FGFR1 interacts with FRS2 constitutively, independent ofligand stimulation and tyrosine phosphorylation, NGF receptor(TrkA) binding to FRS2 is strongly dependent on receptor activation.Complex formation with TrkA is dependent on phosphorylation ofY490, a canonical PTB domain binding site that also functionsas a binding site for Shc (NPXpY). Using deletion and alaninescanning mutagenesis as well as peptide competition assays, wedemonstrate that the PTB domains of the FRS2 proteins specificallyrecognize two different primary structures in two different receptorsin a phosphorylation-dependent or -independent manner. In addition,NGF-induced tyrosine phosphorylation of FRS2 $alpha$ is diminished incells that overexpress a kinase-inactive mutant of FGFR1. Thisexperiment suggests that FGFR1 may regulate signaling via NGFreceptors by sequestering a common key element which both receptorsutilize for transmitting their signals. The multiple interactionsmediated by FRS2 appear to play an important role in target selectionand in defining the specificity of several families of receptortyrosinekinases.

^* Corresponding author. Mailing address: Department of Pharmacology and the Skirball Institute, New York University School ofMedicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-7111.Fax: (212) 263-7133. E-mail: laxidi{at}mcrcrg.med.nyu.edu.

Molecular and Cellular Biology, February 2000, p. 979-989, Vol. 20, No. 3
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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