PMID- 12935294
OWN - NLM
STAT- MEDLINE
DCOM- 20031209
LR  - 20191210
IS  - 1470-8728 (Electronic)
IS  - 0264-6021 (Print)
IS  - 0264-6021 (Linking)
VI  - 376
IP  - Pt 1
DP  - 2003 Nov 15
TI  - Regulation of interleukin-3-induced substrate phosphorylation and cell survival 
      by SHP-2 (Src-homology protein tyrosine phosphatase 2).
PG  - 147-57
AB  - The cytosolic SHP-2 (Src homology protein tyrosine phosphatase 2) has previously 
      been implicated in IL-3 (interleukin-3) signalling [Bone, Dechert, Jirik, 
      Schrader and Welham (1997) J. Biol. Chem. 272, 14470 -14476; Craddock and Welham 
      (1997) J. Biol. Chem. 272, 29281-29289; Welham, Dechert, Leslie, Jirik and 
      Schrader (1994) J. Biol. Chem. 269, 23764-23768; Qu, Nguyen, Chen and Feng (2001) 
      Blood 97, 911-914]. To investigate the role of SHP-2 in IL-3 signalling in 
      greater detail, we have inducibly expressed WT (wild-type) or two potentially 
      substrate-trapping mutant forms of SHP-2, generated by mutation of Asp-425 to Ala 
      (D425A) or Cyst-459 to Ser (C459S), in IL-3-dependent BaF/3 cells. Effects on 
      IL-3-induced tyrosine phosphorylation, signal transduction and functional 
      responses were examined. Expression of C459S SHP-2 protected the beta-chain of 
      the murine IL-3R (IL-3 receptor), the adaptor protein Gab2 (Grb2-associated 
      binder 2), and a cytosolic protein of 48 kDa from tyrosine dephosphorylation, 
      consistent with them being bona fide substrates of SHP-2 in IL-3 signalling. The 
      tyrosine phosphorylation of a 135 kDa transmembrane protein was also protected 
      upon expression of C459S SHP-2. We have identified the inhibitory immunoreceptor 
      PECAM-1 (platelet endothelial cell adhesion molecule-1)/CD31 (cluster determinant 
      31) as a component of this 135 kDa substrate and also show that IL-3 can induce 
      tyrosine phosphorylation of PECAM-1. Expression of WT, C459S and D425A forms of 
      SHP-2 had little effect on IL-3-driven proliferation or STAT5 (signal 
      transduction and activators of transcription) phosphorylation or activation of 
      protein kinase B. However, expression of WT SHP-2 increased ERK 
      (extracellular-signal-regulated kinase) activation. Interestingly, expression of 
      C459S SHP-2 decreased ERK activation at later times after IL-3 stimulation, but 
      potentiated IL-3-induced activation of Jun N-terminal kinases. In addition, 
      expression of C459S SHP-2 decreased cell survival in suboptimal IL-3 and upon 
      IL-3 withdrawal. These findings indicate that SHP-2 plays an important role in 
      mediating the anti-apoptotic effect of IL-3 and raises the possibility that 
      PECAM-1 participates in the modulation of cytokine-induced signals.
FAU - Wheadon, Helen
AU  - Wheadon H
AD  - Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK. 
      m.j.welham@bath.ac.uk
FAU - Edmead, Christine
AU  - Edmead C
FAU - Welham, Melanie J
AU  - Welham MJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem J
JT  - The Biochemical journal
JID - 2984726R
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Gab2 protein, mouse)
RN  - 0 (Interleukin-3)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Milk Proteins)
RN  - 0 (Phosphoproteins)
RN  - 0 (Platelet Endothelial Cell Adhesion Molecule-1)
RN  - 0 (Receptors, Interleukin-3)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (Trans-Activators)
RN  - 144715-96-8 (Csf2rb2 protein, mouse)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
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)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Cell Line
MH  - Cell Survival
MH  - DNA-Binding Proteins/metabolism
MH  - Interleukin-3/*pharmacology
MH  - Intracellular Signaling Peptides and Proteins
MH  - Mice
MH  - *Milk Proteins
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Mutation
MH  - Phosphoproteins/chemistry/metabolism
MH  - Phosphorylation
MH  - Platelet Endothelial Cell Adhesion Molecule-1/metabolism
MH  - Protein Phosphatase 2
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11
MH  - Protein Tyrosine Phosphatases/genetics/metabolism/*physiology
MH  - Receptors, Interleukin-3/metabolism
MH  - STAT5 Transcription Factor
MH  - Trans-Activators/metabolism
MH  - Tyrosine/metabolism
PMC - PMC1223759
EDAT- 2003/08/26 05:00
MHDA- 2003/12/11 05:00
PMCR- 2004/05/15
CRDT- 2003/08/26 05:00
PHST- 2003/08/22 00:00 [accepted]
PHST- 2003/08/20 00:00 [revised]
PHST- 2003/07/31 00:00 [received]
PHST- 2003/08/26 05:00 [pubmed]
PHST- 2003/12/11 05:00 [medline]
PHST- 2003/08/26 05:00 [entrez]
PHST- 2004/05/15 00:00 [pmc-release]
AID - BJ20031160 [pii]
AID - 10.1042/BJ20031160 [doi]
PST - ppublish
SO  - Biochem J. 2003 Nov 15;376(Pt 1):147-57. doi: 10.1042/BJ20031160.