SHP1 protein tyrosine phosphatase negatively modulates erythroid differentiation and suppression of apoptosis in J2E erythroleukemic cells.
The SH2 domain-containing tyrosine phosphatase SHP1 is known to play a crucial role in the regulation of hematopoiesis. It has been shown previously that SHP1 associates with the activated erythropoietin receptor (EPOR) and negatively regulates mitogenic signaling. To further elucidate the role of SHP1 in erythropoietin (EPO)-induced cellular responses we employed J2E erythroleukemic cells as a model for erythroid maturation and cytokine-triggered suppression of apoptosis. Our data indicate that overexpressed SHP1 inhibits both EPO-induced differentiation as well as prevention of apoptosis. The specific signaling pathways responsible are not unraveled so far. Therefore, we analyzed the involvement of SHP1 in two established EPO-stimulated pathways, the JAK/STAT and the MAP kinase cascades, by transient coexpression of reporter constructs containing binding sites for transcription factors targeted by these pathways and a SHP1 cDNA. Both pathways are inhibited by SHP1 as indicated by the lower induction of reporter gene activity. In conclusion, SHP1 regulates the transcriptional activity stimulated by the EPO-induced JAK/STAT and MAPK pathways and is involved in the signaling machinery responsible for erythroid differentiation and suppression of apoptosis.
Bittorf
T
T
Institute of Medical Biochemistry, Medical Faculty, University of Rostock, Germany.
Seiler
J
J
Zhang
Z
Z
Jaster
R
R
Brock
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D017930:Genes, Reporter; D047908:Intracellular Signaling Peptides and Proteins; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D011994:Recombinant Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D004921:Erythropoietin; D020928:Mitogen-Activated Protein Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse