Unique functions for protein kinase D1 and protein kinase D2 in mammalian cells.
Unique functions for protein kinase D1 and protein kinase D2 in mammalian cells.
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DOI：
10.1042/bj20101188
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发表时间：
2010-11-15
期刊：
影响因子：
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通讯作者：
Cantrell DA
中科院分区：
文献类型：
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作者：
Matthews SA;Navarro MN;Sinclair LV;Emslie E;Feijoo-Carnero C;Cantrell DA
哺乳动物PKD（蛋白激酶D）亚型参与调节多种生物学过程，响应于二酰基甘油和PKC（蛋白激酶C）信号传导。为了比较PKD 1和PKD 2在体内的功能，我们通过PKD 1 S744 A/S748 A或PKD 2S 707 A/S711 A“敲入”等位基因的纯合表达产生了PKD 1或PKD 2酶活性缺陷的小鼠。我们还检查了使用“基因陷阱”技术产生的PKD 2缺陷小鼠。我们证明，与PKD 1不同，PKD 2的催化活性对于正常胚胎发生是不稳定的。我们还表明，PKD 2是主要的PKD亚型在淋巴组织中表达，但PKD 2的催化活性是不是必不可少的发展成熟的外周T-和B-淋巴细胞。然而，PKD 2催化活性是T淋巴细胞中有效的抗原受体诱导的细胞因子产生和体内最佳T细胞依赖性抗体应答所必需的。我们的研究结果揭示了PKD 2在适应性免疫应答过程中调节成熟外周淋巴细胞功能的关键体内作用。他们还证实了PKC介导的PKD催化结构域的丝氨酸磷酸化对PKD活化和下游信号传导的功能重要性，并揭示了不同的PKD家族成员在体内具有独特的非冗余作用。
Mammalian PKD (protein kinase D) isoforms have been implicated in the regulation of diverse biological processes in response to diacylglycerol and PKC (protein kinase C) signalling. To compare the functions of PKD1 and PKD2 in vivo, we generated mice deficient in either PKD1 or PKD2 enzymatic activity, via homozygous expression of PKD1S744A/S748A or PKD2S707A/S711A ‘knockin’ alleles. We also examined PKD2-deficient mice generated using ‘gene-trap’ technology. We demonstrate that, unlike PKD1, PKD2 catalytic activity is dispensable for normal embryogenesis. We also show that PKD2 is the major PKD isoform expressed in lymphoid tissues, but that PKD2 catalytic activity is not essential for the development of mature peripheral T- and B-lymphocytes. PKD2 catalytic activity is, however, required for efficient antigen receptor-induced cytokine production in T-lymphocytes and for optimal T-cell-dependent antibody responses in vivo. Our results reveal a key in vivo role for PKD2 in regulating the function of mature peripheral lymphocytes during adaptive immune responses. They also confirm the functional importance of PKC-mediated serine phosphorylation of the PKD catalytic domain for PKD activation and downstream signalling and reveal that different PKD family members have unique and non-redundant roles in vivo.