PMID- 12402043
OWN - NLM
STAT- MEDLINE
DCOM- 20040414
LR  - 20131121
IS  - 1465-7392 (Print)
IS  - 1465-7392 (Linking)
VI  - 4
IP  - 11
DP  - 2002 Nov
TI  - Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling 
      pathway.
PG  - 850-8
AB  - Sprouty (Spry) inhibits signalling by receptor tyrosine kinases; however, the 
      molecular mechanism underlying this function has not been defined. Here we show 
      that after stimulation by growth factors Spry1 and Spry2 translocate to the 
      plasma membrane and become phosphorylated on a conserved tyrosine. Next, they 
      bind to the adaptor protein Grb2 and inhibit the recruitment of the Grb2-Sos 
      complex either to the fibroblast growth factor receptor (FGFR) docking adaptor 
      protein FRS2 or to Shp2. Membrane translocation of Spry is necessary for its 
      phosphorylation, which is essential for its inhibitor activity. A 
      tyrosine-phosphorylated octapeptide derived from mouse Spry2 inhibits Grb2 from 
      binding FRS2, Shp2 or mouse Spry2 in vitro and blocks activation of the 
      extracellular-signal-regulated kinase (ERK) in cells stimulated by growth factor. 
      A non-phosphorylated Spry mutant cannot bind Grb2 and acts as a dominant 
      negative, inducing prolonged activation of ERK in response to FGF and promoting 
      the FGF-induced outgrowth of neurites in PC12 cells. Our findings suggest that 
      Spry functions in a negative feedback mechanism in which its inhibitor activity 
      is controlled rapidly and reversibly by post-translational mechanisms.
FAU - Hanafusa, Hiroshi
AU  - Hanafusa H
AD  - Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, 
      Kyoto 606-8502, Japan.
FAU - Torii, Satoru
AU  - Torii S
FAU - Yasunaga, Takayuki
AU  - Yasunaga T
FAU - Nishida, Eisuke
AU  - Nishida E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nat Cell Biol
JT  - Nature cell biology
JID - 100890575
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (DNA, Complementary)
RN  - 0 (FRS2 protein, human)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Peptides)
RN  - 0 (Phosphoproteins)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 0 (SPRY1 protein, human)
RN  - 0 (Spry1 protein, mouse)
RN  - 0 (Spry2 protein, rat)
RN  - 42HK56048U (Tyrosine)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.48 (PTPN11 protein, human)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
RN  - EC 3.1.3.48 (Ptpn11 protein, mouse)
RN  - EC 3.1.3.48 (Ptpn11 protein, rat)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding, Competitive
MH  - COS Cells
MH  - Cattle
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - DNA, Complementary/metabolism
MH  - Dimerization
MH  - Enzyme Activation
MH  - Genes, Dominant
MH  - HeLa Cells
MH  - Humans
MH  - Immunoblotting
MH  - Intracellular Signaling Peptides and Proteins
MH  - Luciferases/metabolism
MH  - *MAP Kinase Signaling System
MH  - Membrane Proteins/metabolism/*physiology
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Nerve Tissue Proteins/*physiology
MH  - Neurons/metabolism
MH  - PC12 Cells
MH  - Peptides/chemistry
MH  - Phosphoproteins/metabolism/*physiology
MH  - Phosphorylation
MH  - Plasmids/metabolism
MH  - Precipitin Tests
MH  - Protein Binding
MH  - Protein Processing, Post-Translational
MH  - Protein Transport
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11
MH  - Protein Tyrosine Phosphatases/metabolism
MH  - Rats
MH  - Receptors, Fibroblast Growth Factor/metabolism
MH  - Sequence Homology, Amino Acid
MH  - Time Factors
MH  - Tyrosine/chemistry/metabolism
MH  - Xenopus
MH  - ras Proteins/*metabolism
EDAT- 2002/10/29 04:00
MHDA- 2004/04/15 05:00
CRDT- 2002/10/29 04:00
PHST- 2002/05/14 00:00 [received]
PHST- 2002/07/22 00:00 [revised]
PHST- 2002/08/15 00:00 [accepted]
PHST- 2002/10/29 04:00 [pubmed]
PHST- 2004/04/15 05:00 [medline]
PHST- 2002/10/29 04:00 [entrez]
AID - ncb867 [pii]
AID - 10.1038/ncb867 [doi]
PST - ppublish
SO  - Nat Cell Biol. 2002 Nov;4(11):850-8. doi: 10.1038/ncb867.