Takahashi-Tezuka M, Hibi M, Fujitani Y, Fukada T, Yamaguchi T, Hirano T
Department of Molecular Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Japan.
Oncogene. 1997 May 15;14(19):2273-82. doi: 10.1038/sj.onc.1201071.
Tec/Btk tyrosine kinases are members of a subgroup of Src tyrosine kinase family. They are reported to be activated in response to cytokines, such as IL-3 and IL-6. Janus kinases (JAKs) are known to associate with certain cytokine receptors, e.g. gp130, the signal transducing subunit of IL-6 receptor, and the common beta chain of IL-3 receptor, which can be activated upon receptor dimerization in response to cytokines. Here we show the association between Jak1/Jak2 and Tec or Jak1 and Btk. Furthermore, Jak1 but not Jak2 induces tyrosine phosphorylation of Btk, but not Tec. These observations suggest that upon cytokine stimulation JAKs activate Tec/Btk or induce their dimerization resulting in endogenous tyrosine phosphorylation. Furthermore using a yeast two-hybrid system we have identified the target molecules for Tec, the p85 and p55PIK subunits of PI-3 kinase, and Vav. Tec associated with Vav through its SH2 domain independently of its kinase activity. In contrast the p85 and p55PIK subunits of PI-3 kinase associated with the SH2-kinase domain of Tec, dependent on Tec kinase activity. Consistent with these, IL-6 or IL-3 induced the association between Tec and the p85 subunit of PI-3 kinase in mammalian cells. These findings suggest that Tec tyrosine kinase links cytokine receptors to PI-3 kinase probably through JAKs.
Tec/Btk酪氨酸激酶是Src酪氨酸激酶家族一个亚组的成员。据报道，它们可因白细胞介素-3和白细胞介素-6等细胞因子而被激活。已知Janus激酶（JAKs）与某些细胞因子受体相关联，例如白细胞介素-6受体的信号转导亚基gp130以及白细胞介素-3受体的共同β链，这些受体在细胞因子作用下发生二聚化时可被激活。在此我们展示了Jak1/Jak2与Tec之间以及Jak1与Btk之间的关联。此外，Jak1而非Jak2可诱导Btk的酪氨酸磷酸化，但不能诱导Tec的酪氨酸磷酸化。这些观察结果表明，在细胞因子刺激下，JAKs激活Tec/Btk或诱导其发生二聚化，从而导致内源性酪氨酸磷酸化。此外，我们利用酵母双杂交系统鉴定出了Tec的靶分子，即PI-3激酶的p85和p55PIK亚基以及Vav。Tec通过其SH2结构域与Vav结合，这与其激酶活性无关。相比之下，PI-3激酶的p85和p55PIK亚基与Tec的SH2-激酶结构域结合，依赖于Tec激酶活性。与此一致的是，白细胞介素-6或白细胞介素-3在哺乳动物细胞中诱导了Tec与PI-3激酶p85亚基之间的结合。这些发现表明，Tec酪氨酸激酶可能通过JAKs将细胞因子受体与PI-3激酶联系起来。
