Inhibition of erythropoietin-induced mitogenesis by a kinase-deficient form of Jak2.
Receptors for a variety of hematopoietins, interferons alpha/beta and gamma, and growth hormone have recently been shown to mediate rapid, ligand-dependent activation of the Janus-type cytosolic protein-tyrosine kinases Jak1, Jak2, and/or tyk-2. This finding extends relatedness among class I and II cytokine receptors to a functional context and provides an initially satisfying mechanistic analogy to protein-tyrosine kinase-encoding receptors of the epidermal growth factor/platelet-derived growth factor/insulin family. Through the construction and expression of a kinase-deficient form of Jak2 (JK2 delta VIII) in interleukin-3 (IL-3)/erythropoietin (Epo)-dependent DAER cells, we have tested whether activation of Jak2 is required for induced mitogenesis via these class I cytokine receptors. Ectopic expression of JK2 delta VIII inhibited Epo- and IL-3-induced activation of endogenous wild-type Jak2, transiently attenuated IL-3-dependent growth, and essentially abrogated Epo-induced proliferation in this model system. These dominant-negative effects provide the first direct experimental evidence for an essential role for Janus kinase activation in mitogenesis and suggest that distinct effectors may mediate IL-3-induced versus Epo-induced pathways.
Zhuang
H
H
Department of Biochemistry, Pennsylvania State University, University Park 16802.
Patel
S V
SV
He
T C
TC
Sonsteby
S K
SK
Niu
Z
Z
Wojchowski
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004921:Erythropoietin / Q000494:pharmacology*; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2; D008934:Mitogens / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3 / Q000378:metabolism; D015398:Signal Transduction
D007377:Interleukin-3; D008934:Mitogens; D011518:Proto-Oncogene Proteins; D016185:Receptors, Interleukin-3; D004921:Erythropoietin; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2