PMID- 10629055
OWN - NLM
STAT- MEDLINE
DCOM- 20000214
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 20
IP  - 3
DP  - 2000 Feb
TI  - FRS2 proteins recruit intracellular signaling pathways by binding to diverse
      targets on fibroblast growth factor and nerve growth factor receptors.
PG  - 979-89
AB  - 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, FRS2alpha and FRS2beta, 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 alpha
      and beta 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 FRS2alpha 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.
FAU - Ong, S H
AU  - Ong SH
AD  - Signal Transduction Laboratory, Institute of Molecular and Cell Biology,
      Singapore 117609, Singapore.
FAU - Guy, G R
AU  - Guy GR
FAU - Hadari, Y R
AU  - Hadari YR
FAU - Laks, S
AU  - Laks S
FAU - Gotoh, N
AU  - Gotoh N
FAU - Schlessinger, J
AU  - Schlessinger J
FAU - Lax, I
AU  - Lax I
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (FRS2 protein, human)
RN  - 0 (GRB2 Adaptor Protein)
RN  - 0 (GRB2 protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 0 (Receptors, Nerve Growth Factor)
RN  - 0 (Recombinant Proteins)
RN  - EC 2.7.10.1 (FGFR1 protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
RN  - EC 3.1.3.48 (PTPN11 protein, human)
RN  - EC 3.1.3.48 (PTPN6 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 6)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
RN  - EC 3.1.3.48 (SH2 Domain-Containing Protein Tyrosine Phosphatases)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Cell Line
MH  - GRB2 Adaptor Protein
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Membrane Proteins/*metabolism
MH  - Molecular Sequence Data
MH  - Mutagenesis
MH  - Phosphoproteins/*metabolism
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 1
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6
MH  - Protein Tyrosine Phosphatases/chemistry/metabolism
MH  - Proteins/chemistry/metabolism
MH  - Receptor Protein-Tyrosine Kinases/chemistry/genetics/*metabolism
MH  - Receptor, Fibroblast Growth Factor, Type 1
MH  - Receptors, Fibroblast Growth Factor/chemistry/genetics/*metabolism
MH  - Receptors, Nerve Growth Factor/chemistry/*metabolism
MH  - Recombinant Proteins/chemistry/metabolism
MH  - SH2 Domain-Containing Protein Tyrosine Phosphatases
MH  - Sequence Alignment
MH  - Sequence Deletion
MH  - Sequence Homology, Amino Acid
MH  - Signal Transduction/*physiology
MH  - Transfection
MH  - src Homology Domains
PMC - PMC85215
EDAT- 2000/01/11 09:00
MHDA- 2000/02/19 09:00
CRDT- 2000/01/11 09:00
PHST- 2000/01/11 09:00 [pubmed]
PHST- 2000/02/19 09:00 [medline]
PHST- 2000/01/11 09:00 [entrez]
AID - 10.1128/mcb.20.3.979-989.2000 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2000 Feb;20(3):979-89. doi: 10.1128/mcb.20.3.979-989.2000.