Catalytic-dependent and -independent roles of SHP-2 tyrosine phosphatase in interleukin-3 signaling.
SHP-2 tyrosine phosphatase is highly expressed in hematopoietic cells, however, the function of SHP-2 in hematopoietic cell signaling is not well understood. Here we focus on the role of SHP-2 phosphatase in the signal transduction of interleukin (IL)-3, a cytokine involved in hematopoietic cell survival, proliferation, and differentiation. We established immortalized SHP-2(-/-) hematopoietic cell pools and showed that IL-3-induced proliferative response was diminished in SHP-2(-/-) cells. Moreover, inhibition of the catalytic activity of SHP-2 in wild-type (WT) bone marrow hematopoietic progenitor cells and Ba/F3 cells by overexpression of catalytically inactive SHP-2 mutant suppressed their differentiative and proliferative responses to IL-3, demonstrating an important positive role for SHP-2 in IL-3 signal transduction. Further biochemical analyses revealed that IL-3-induced Jak/Stat, Erk, and PI3 kinase pathways in SHP-2(-/-) cells were impaired and reintroduction of WT SHP-2 into mutant cells partially restored IL-3 signaling. Interestingly, in catalytically inactive SHP-2-overexpressing Ba/F3 cells, although IL-3-induced activation of Jak2 and Erk kinases was reduced and shortened, PI3 kinase activation remained unaltered. Taken together, these results suggest that SHP-2 tyrosine phosphatase plays multiple roles in IL-3 signal transduction, functioning in both catalytic-dependent and -independent manners in the Jak/Stat, Erk, and PI3 kinase pathways.
Yu
Wen-Mei
WM
Department of Hematopoiesis, Jerome H Holland Laboratory for the Biomedical Sciences, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855, USA.
Hawley
Teresa S
TS
Hawley
Robert G
RG
Qu
Cheng-Kui
CK
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002384:Catalysis; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D018014:Gene Transfer Techniques; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007377:Interleukin-3 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D051379:Mice; D008817:Mice, Mutant Strains; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C490897:Gab1 protein, mouse; C487378:Tlx1 protein, mouse; C507926:Jak2 protein, mouse; C516725:Ptpn11 protein, mouse