Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction.
Binding of interleukin (IL)-4 to its transmembrane receptor results in the Jak-mediated tyrosine phosphorylation of a number of protein components of the IL-4 signaling cascade, including Jak1, Jak2, Jak3, Tyk2, IL-4Ralpha, IRS-1, IRS-2, and Stat6 in appropriate cell types. However, the protein-tyrosine phosphatases (PTPs) that dephosphorylate these proteins and terminate signaling remained unidentified. We have noted that IL-4-dependent activation of Stat6 is sustained longer in fibroblasts than in lymphoid cells. Because Shp-1, an SH2 domain-containing PTP, is expressed primarily in hematopoietic cells, we examined whether Shp-1 activity could regulate IL-4-dependent cell signaling. Expression of an Shp-1 transgene in NIH 3T3 cells markedly reduces both IL-4-dependent Stat6 activation and Stat6-mediated transcription of IL-4-responsive genes. In accord with this, IL-4 treatment of bone marrow-derived macrophages from viable motheaten mice that express substantially reduced levels of Shp-1 activity show remarkably enhanced activation of Stat6. In addition, Stat6 activation by IL-4 is significantly enhanced in pre-B cells derived from motheaten (Shp-1 null mutant) mice compared with normal pre-B cells derived from control animals. These data clearly implicate Shp-1 in the negative regulation of the IL-4/IL-13-activated Jak-Stat pathway.
Haque
S J
SJ
Department of Cancer Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. haquej@cesmtp.ccf.org
Harbor
P
P
Tabrizi
M
M
Yi
T
T
Williams
B R
BR
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D018909:src Homology Domains
D018793:Interleukin-13; D047908:Intracellular Signaling Peptides and Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases