An epidermal growth factor receptor/Jak2 tyrosine kinase domain chimera induces tyrosine phosphorylation of Stat5 and transduces a growth signal in hematopoietic cells.
The Jak family of tyrosine kinases and the Stat family of transcription factors have been implicated in transducing signals from the hematopoietic growth factor receptors. To explore the role played by a member of the Jak family, Jak2, in hematopoietic cell growth signaling, we constructed a chimeric cDNA coding for the Jak2 tyrosine kinase domain linked to the extracellular and transmembrane regions of the epidermal growth factor (EGF) receptor (EGFR) and expressed the chimera in an interleukin (IL)-3-dependent cell line, 32D. When deprived of IL-3, EGF prevented apoptosis of the transfected cells, induced dose-dependent proliferation, and supported long-term growth. EGF stimulation of the transfectants induced dose-dependent tyrosine phosphorylation of the EGFR/Jak2 chimera and Stat5, which correlated with the EGF dose dependence of cell proliferation. On the other hand, EGF did not induce tyrosine phosphorylation of other factors implicated in cytokine receptor signaling, including the IL-3 receptor beta subunit, Jak kinases, Stat proteins other than Stat5, Shc, Syp, and mitogen-activated protein kinases. These results suggest that the activation of Jak2 may be sufficient for transducing a growth signal in hematopoietic cells by activating the Stat5 pathway or previously unidentified signaling pathways. In addition, because EGF induces homodimerization of the EGFR to activate its tyrosine kinase activity, the present study, which shows EGF-dependent activation of the EGFR/Jak2 chimera, implies that Jak2 may also become activated by homodimerization.
Nakamura
N
N
First Department of Internal Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan.
Chin
H
H
Miyasaka
N
N
Miura
O
O
D001483:Base Sequence; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D053614:Janus Kinase 2; D008894:Milk Proteins; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2