Deb Dilip K, Sassano Antonella, Lekmine Fatima, Majchrzak Beata, Verma Amit, Kambhampati Suman, Uddin Shahab, Rahman Arshad, Fish Eleanor N, Platanias Leonidas C
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Northwestern University Medical School, Chicago, IL 60611, USA.
J Immunol. 2003 Jul 1;171(1):267-73. doi: 10.4049/jimmunol.171.1.267.
Engagement of the type II IFN (IFN-gamma) receptor results in activation of the Janus kinase-Stat pathway and induction of gene transcription via IFN-gamma-activated site (GAS) elements in the promoters of IFN-gamma-inducible genes. An important event in IFN-gamma-dependent gene transcription is phosphorylation of Stat1 on Ser(727), which is regulated by a kinase activated downstream of the phosphatidylinositol 3'-kinase. Here we provide evidence that a member of the protein kinase C (PKC) family of proteins is activated downstream of the phosphatidylinositol 3'-kinase and is engaged in IFN-gamma signaling. Our data demonstrate that PKCdelta is rapidly phosphorylated during engagement of the type II IFNR and its kinase domain is induced. Subsequently, the activated PKCdelta associates with a member of the Stat family of proteins, Stat1, which acts as a substrate for its kinase activity and undergoes phosphorylation on Ser(727). Inhibition of PKCdelta activity diminishes phosphorylation of Stat1 on Ser(727) and IFN-gamma-dependent transcriptional regulation via IFN-gamma-activated site elements, without affecting the phosphorylation of the protein on Tyr(701). Thus, PKCdelta is activated during engagement of the IFN-gamma receptor and plays an important role in IFN-gamma signaling by mediating serine phosphorylation of Stat1 and facilitating transcription of IFN-gamma-stimulated genes.
II型干扰素（IFN-γ）受体的激活会导致Janus激酶-Stat信号通路的活化，并通过IFN-γ诱导基因启动子中的IFN-γ激活位点（GAS）元件诱导基因转录。IFN-γ依赖性基因转录中的一个重要事件是Stat1在Ser（727）位点的磷酸化，这受磷脂酰肌醇3'-激酶下游激活的一种激酶调控。在此，我们提供证据表明，蛋白激酶C（PKC）家族的一个成员在磷脂酰肌醇3'-激酶下游被激活，并参与IFN-γ信号传导。我们的数据表明，在II型IFNR激活过程中PKCδ迅速磷酸化，其激酶结构域被诱导。随后，活化的PKCδ与Stat家族蛋白成员Stat1结合，Stat1作为其激酶活性的底物，在Ser（727）位点发生磷酸化。抑制PKCδ活性会减少Stat1在Ser（727）位点的磷酸化以及通过IFN-γ激活位点元件的IFN-γ依赖性转录调控，而不影响该蛋白在Tyr（701）位点的磷酸化。因此，PKCδ在IFN-γ受体激活过程中被激活，并通过介导Stat1的丝氨酸磷酸化和促进IFN-γ刺激基因的转录在IFN-γ信号传导中发挥重要作用。
