Interleukin 3 and erythropoietin induce association of Vav with Tec kinase through Tec homology domain.
Although hematopoietic cytokine receptors lack tyrosine kinase domains, the binding of their ligands to the receptors induce rapid tyrosine phosphorylation of various cellular target proteins. The specific tyrosine kinases which phosphorylate these substrates, however, have not been identified, other than that JAK kinases which phosphorylate STAT proteins and the receptors. We found that the c-vav proto-oncogene product, Vav, is rapidly and transiently tyrosine-phosphorylated in response to erythropoietin and IL3 stimulations and that Tec kinase is also transiently activated by these cytokines. Immunoprecipitation experiments demonstrated that Tec kinase binds to Vav upon these cytokine stimulations and that Grb2 constitutively associates with Vav. In vitro binding assays showed that erythropoietin and IL3 stimulation induce the specific binding of Vav to Tec kinase through Tec homology domains. We therefore concluded that Tec kinase is one of the key enzymes in Epo and IL3 receptor-mediated signaling pathways and that Vav plays an important role in the cytokine receptor-mediated signal transduction.
Machide
M
M
Tsukuba Life Science Center, Institute of Physical and Chemical Research (RIKEN), Ibaraki, Japan.
Mano
H
H
Todokoro
K
K
D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002460:Cell Line; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism; D006412:Hematopoietic Stem Cells; D007377:Interleukin-3 / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000302:isolation & purification / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011519:Proto-Oncogenes; D017467:Receptors, Erythropoietin / Q000502:physiology; D016185:Receptors, Interleukin-3 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D017467:Receptors, Erythropoietin; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; C496619:Vav1 protein, mouse; D004921:Erythropoietin; D005982:Glutathione Transferase; C089848:Tec protein-tyrosine kinase; D011505:Protein-Tyrosine Kinases