PMID- 10022928
OWN - NLM
STAT- MEDLINE
DCOM- 19990325
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 3
DP  - 1999 Mar
TI  - Shp-2 tyrosine phosphatase functions as a negative regulator of the
      interferon-stimulated Jak/STAT pathway.
PG  - 2416-24
AB  - Shp-2 is an SH2 domain-containing protein tyrosine phosphatase. Although the
      mechanism remains to be defined, substantial experimental data suggest that Shp-2
      is primarily a positive regulator in cell growth and development. We present
      evidence here that Shp-2, while acting to promote mitogenic signals, also
      functions as a negative effector in interferon (IFN)-induced growth-inhibitory
      and apoptotic pathways. Treatment of mouse fibroblast cells lacking a functional 
      Shp-2 with IFN-alpha or IFN-gamma resulted in an augmented suppression of cell
      viability compared to that of wild-type cells. To dissect the molecular
      mechanism, we examined IFN-induced activation of signal transducers and
      activators of transcription (STATs) by electrophoretic mobility shift assay,
      using a specific DNA probe (hSIE). The amounts of STAT proteins bound to hSIE
      upon IFN-alpha or IFN-gamma stimulation were significantly increased in
      Shp-2(-/-) cells. Consistently, tyrosine phosphorylation levels of Stat1 upon
      IFN-gamma treatment and, to a lesser extent, upon IFN-alpha stimulation were
      markedly elevated in mutant cells. Furthermore, IFN-gamma induced a higher level 
      of caspase 1 expression in Shp-2(-/-) cells than in wild-type cells.
      Reintroduction of wild-type Shp-2 protein reversed the hypersensitivity of
      Shp-2(-/-) fibroblasts to the cytotoxic effect of IFN-alpha and IFN-gamma.
      Excessive activation of STATs by IFNs was also diminished in mutant cells in
      which Shp-2 had been reintroduced. Together, these results establish that Shp-2
      functions as a negative regulator of the Jak/STAT pathway. We propose that Shp-2 
      acts to promote cell growth and survival through two mechanisms, i.e., the
      stimulation of growth factor-initiated mitogenic pathways and the suppression of 
      cytotoxic effect elicited by cytokines, such as IFNs.
FAU - You, M
AU  - You M
AD  - Department of Biochemistry and Molecular Biology, Walther Oncology Center,
      Indiana University School of Medicine, Indianapolis, Indiana 46202-5254, USA.
FAU - Yu, D H
AU  - Yu DH
FAU - Feng, G S
AU  - Feng GS
LA  - eng
GR  - R29 GM053660/GM/NIGMS NIH HHS/United States
GR  - R29GM53660/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Interferon-alpha)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Interferon)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 0 (STAT2 Transcription Factor)
RN  - 0 (Stat1 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 07MXG07O12 (interferon gamma receptor)
RN  - 156986-95-7 (Receptor, Interferon alpha-beta)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK1 protein, human)
RN  - EC 2.7.10.2 (Jak1 protein, mouse)
RN  - EC 2.7.10.2 (Janus Kinase 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 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 (Ptpn11 protein, mouse)
RN  - EC 3.1.3.48 (Ptpn6 protein, mouse)
RN  - EC 3.1.3.48 (SH2 Domain-Containing Protein Tyrosine Phosphatases)
RN  - EC 3.4.22.36 (Caspase 1)
SB  - IM
MH  - Animals
MH  - Caspase 1/metabolism
MH  - Cell Line
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - Enzyme Induction
MH  - Fibroblasts/cytology/metabolism
MH  - Humans
MH  - Interferon-alpha/*metabolism/pharmacology/toxicity
MH  - Interferon-gamma/*metabolism/pharmacology/toxicity
MH  - Intracellular Signaling Peptides and Proteins
MH  - Janus Kinase 1
MH  - Membrane Proteins
MH  - Mice
MH  - Mutagenesis
MH  - Phenotype
MH  - Phosphorylation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 6
MH  - Protein Tyrosine Phosphatases/genetics/*physiology
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - Receptor, Interferon alpha-beta
MH  - Receptors, Interferon/metabolism
MH  - SH2 Domain-Containing Protein Tyrosine Phosphatases
MH  - STAT1 Transcription Factor
MH  - STAT2 Transcription Factor
MH  - *Signal Transduction
MH  - Trans-Activators/genetics/*metabolism
PMC - PMC84034
EDAT- 1999/02/18 00:00
MHDA- 1999/02/18 00:01
CRDT- 1999/02/18 00:00
PHST- 1999/02/18 00:00 [pubmed]
PHST- 1999/02/18 00:01 [medline]
PHST- 1999/02/18 00:00 [entrez]
AID - 10.1128/mcb.19.3.2416 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Mar;19(3):2416-24. doi: 10.1128/mcb.19.3.2416.