Chemokines integrate JAK/STAT and G-protein pathways during chemotaxis and calcium flux responses
Chemokines integrate JAK/STAT and G-protein pathways during chemotaxis and calcium flux responses
复制标题
DOI：
10.1002/eji.200323897
复制
发表时间：
2003-05-01
影响因子：
5.4
通讯作者：
Mellado, M
中科院分区：
文献类型：
--
作者：
Soriano, SF;Serrano, A;Mellado, M
JAK/STAT（Janus激酶/信号转导子和转录激活子）信号传导途径涉及将静止上皮细胞转化为迁移细胞。在哺乳动物中，迁移反应由包括趋化因子在内的趋化蛋白激活。我们发现，通过与七跨膜G蛋白偶联受体结合，趋化因子激活JAK/STAT通路以触发趋化反应。我们表明，趋化因子介导的JAK/STAT激活是G蛋白诱导和磷脂酶C-β依赖的Ca 2+流量的关键;此外，药理学抑制JAK或突变的JAK激酶结构域导致的缺陷，在这两种反应。此外，Ga（i）与受体的结合依赖于JAK活化，并且需要磷脂酶C-β活性的趋化因子介导的Ca 2+通量发生在JAK激酶的下游。因此，趋化因子采用一种机制，连接异源信号通路- G蛋白和酪氨酸激酶-在一个网络中，可能是必不可少的介导他们的多效性反应。
The JAK/STAT (Janus kinase / signaling transducer and activator of transcription) signaling pathway is implicated in converting stationary epithelial cells to migratory cells. In mammals, migratory responses are activated by chemoattractant proteins, including chemokines. We found that by binding to seven-transmembrane G-protein-coupled receptors, chemokines activate the JAK/STAT pathway to trigger chemotactic responses. We show that chemokine-mediated JAK/STAT activation is critical for G-protein induction and for phospholipase C-beta dependent Ca2+ flux; in addition, pharmacological inhibition of JAK or mutation of the JAK kinase domain causes defects in both responses. Furthermore, Galpha(i) association with the receptor is dependent on JAK activation, and the chemokine-mediated Ca2+ flux that requires phospholipase C-beta activity takes place downstream of JAK kinases. The chemokines thus employ a mechanism that links heterologous signaling pathways - G proteins and tyrosine kinases - in a network that may be essential for mediating their pleiotropic responses.