Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration.
Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration.
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DOI：
10.1126/scisignal.2002006
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发表时间：
2011-08-23
影响因子：
7.3
通讯作者：
Tsichlis PN
中科院分区：
文献类型：
--
作者：
Hatziapostolou M;Koukos G;Polytarchou C;Kottakis F;Serebrennikova O;Kuliopulos A;Tsichlis PN
丝裂原激活蛋白激酶激酶激酶 (MAPKKK) 肿瘤进展位点 2 (Tpl2) 是凝血酶激活 G 蛋白偶联受体 (GPCR) 蛋白酶激活受体 1 (PAR1) 启动信号转导所必需的，可促进肌动蛋白细胞骨架重组和细胞迁移。在这里，我们证明 Tpl2 通过 Gαi2 转导的 GPCR 信号被激活。激活的 Tpl2 促进磷脂酶 C beta 3 (PLCβ3) 的磷酸化和激活，因此，Tpl2 是凝血酶依赖性肌醇 1,4,5-三磷酸 (IP3) 的产生、细胞质 Ca2+ 的上调以及蛋白激酶 C (PKC) 家族经典和新成员的激活所必需的。 PKC 反馈环路可响应 Tpl2 促进细胞外信号调节激酶 (ERK) 激活，并有助于 ERK 和 Ca2+ 信号通路的协调调节。药理学和遗传学研究表明，Tpl2 对细胞迁移的刺激取决于这两种途径。 Tpl2 还促进 Ca2+ 信号和来自 Gαi 偶联 GPCR（除 PAR1 外）和 IL-1β 受体的细胞迁移。我们的数据为 Tpl2 在 GPCR 介导的 Ca2+ 信号传导和细胞迁移中的作用提供了新的见解。此外，它们还增强了我们对 Tpl2 在先天性和适应性免疫、癌症和炎症中基本作用的理解。
The mitogen-activated protein kinase kinase kinase (MAPKKK) tumor progression locus 2 (Tpl2) is required for the transduction of signals initiated by the thrombin-activated G protein-coupled receptor (GPCR) protease activated receptor-1 (PAR1), which promote reorganization of the actin cytoskeleton and cell migration. Here, we show that Tpl2 is activated through Gαi2-transduced GPCR signals. Activated Tpl2 promotes the phosphorylation and activation of phospholipase C beta 3 (PLCβ3) and, concsequently, Tpl2 is required for thrombin-dependent production of inositol 1,4,5-triphosphate (IP3), the upregulation of cytoplasmic Ca2+, and the activation of classical and novel members of the protein kinase C (PKC) family. A PKC feedback loop facilitates extracellular signal-regulated kinase (ERK) activation in response to Tpl2 and contributes to the coordinate regulation of the ERK and Ca2+ signaling pathways. Pharmacological and genetic studies revealed that stimulation of cell migration by Tpl2 depends on both of these pathways. Tpl2 also promoted Ca2+ signals and cell migration from Gαi-coupled GPCRs other than PAR1, and from the IL-1β receptor. Our data provide new insights into the role of Tpl2 in GPCR-mediated Ca2+ signaling and cell migration. In addition, they enhance our understanding of the fundamental role of Tpl2 in innate and adaptive immunity, cancer and inflammation.
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影响因子：
11.2
作者：
Hatziapostolou, Maria;Polytarchou, Christos;Tsichlis, Philip N.
通讯作者：
Tsichlis, Philip N.
影响因子：
7.3
作者：
Iliopoulos D;Polytarchou C;Hatziapostolou M;Kottakis F;Maroulakou IG;Struhl K;Tsichlis PN
通讯作者：
Tsichlis PN
影响因子：
4
作者：
Joslin, Elizabeth J.;Opresko, Lee K.;Lauffenburger, Douglas A.
通讯作者：
Lauffenburger, Douglas A.
影响因子：
64.8
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
64.8
作者：
Coughlin, SR
通讯作者：
Coughlin, SR