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Molecular and Cellular Biology, February 2000, p. 979-989, Vol. 20, No. 3
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-activated protein
kinase signaling cascade. The two members of the FRS2 family, FRS2
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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
and FRS2
, are structurally very similar. Each is composed of an
N-terminal myristylation signal, a phosphotyrosine-binding (PTB)
domain, and a C-terminal tail containing multiple binding sites for the
SH2 domains of the adapter protein Grb2 and the protein tyrosine
phosphatase Shp2. Here we show that the PTB domains of both the
and
isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB
domains of the FRS2 proteins bind to a highly conserved sequence in the
juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2
constitutively, independent of ligand stimulation and tyrosine
phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly
dependent on receptor activation. Complex formation with TrkA is
dependent on phosphorylation of Y490, a canonical PTB domain binding
site that also functions as a binding site for Shc (NPXpY).
Using deletion and alanine scanning mutagenesis as well as peptide
competition assays, we demonstrate that the PTB domains of the FRS2
proteins specifically recognize two different primary structures in two
different receptors in a phosphorylation-dependent or -independent
manner. In addition, NGF-induced tyrosine phosphorylation of FRS2
is
diminished in cells that overexpress a kinase-inactive mutant of FGFR1.
This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.
*
Corresponding author. Mailing address: Department of
Pharmacology and the Skirball Institute, New York University School of Medicine, 550 First Ave., New York, NY 10016. Phone: (212) 263-7111. Fax: (212) 263-7133. E-mail: laxidi{at}mcrcrg.med.nyu.edu.
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