Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulin-dependent protein kinases I/IV
Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulin-dependent protein kinases I/IV
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DOI：
10.1074/jbc.m513212200
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发表时间：
2006-07-21
影响因子：
4.8
通讯作者：
Bito, Haruhiko
中科院分区：
文献类型：
--
作者：
Ohmae, Shogo;Takemoto-Kimura, Sayaka;Bito, Haruhiko
尽管钙离子/钙调蛋白（CaM）依赖性蛋白激酶（CaMK）II信号在神经可塑性中至关重要，但迄今为止，关于另一个主要CaMK亚家族CaMKI/CaMKIV家族在中枢神经系统中的存在和意义，只有有限的工作。我们在这里寻找具有与CaMKI和CaMKIV相似的核心催化结构的激酶。我们分离了编码三种小鼠CaMKI/CaMKIV相关激酶的全长cDNA，CLICK-I（CL 1）/双皮质素和CaM激酶样（DCAMKL）1、CLICK-II（CL 2）/DCAMKL 2和CLICK-I，II相关（CLr）/DCAMKL 3，其激酶结构域不仅与CaMKI/CaMKIV而且与CaMKII具有中等同源性。此外，CL 1，CL 2和CLr高度表达在中枢神经系统中，在神经元特异性的方式。CL 1 α和CL 1 β是DCAMKL 1的较短同种型，其缺乏双皮质素样结构域（Dx）。相比之下，CL 2 α和CL 2 β含有完整的N-末端Dx，而CLr仅具有部分和功能失调的Dx。有趣的是，尽管在激酶结构域中有很大的相似性，但CL 1/CL 2/CLr对CRE依赖性基因表达的影响与相关的CaMKI/CaMKIV和CaMKII不同。虽然这些以前被证明激活钙/cAMP反应元件结合蛋白（CREB）依赖的转录，我们在这里表明，CL 1和CL 2不能显着磷酸化CREB Ser-133，而是抑制CREB依赖的基因表达的显性机制，绕过CREB和磷酸化的TORC 2介导的。
Despite the critical importance of Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) II signaling in neuroplasticity, only a limited amount of work has so far been available regarding the presence and significance of another predominant CaMK subfamily, the CaMKI/CaMKIV family, in the central nervous system. We here searched for kinases with a core catalytic structure similar to CaMKI and CaMKIV. We isolated full-length cDNAs encoding three mouse CaMKI/CaMKIV-related kinases, CLICK-I (CL1)/doublecortin and CaM kinase-Like (DCAMKL)1, CLICK-II (CL2)/DCAMKL2, and CLICK-I, II-related (CLr)/DCAMKL3, the kinase domains of which had an intermediate homology not only to CaMKI/CaMKIV but also to CaMKII. Furthermore, CL1, CL2, and CLr were highly ;expressed in the central nervous system, in a neuron-specific fashion. CL1 alpha and CL1 beta were shorter isoforms of DCAMKL1, which lacked the doublecortin-like domain (Dx). In contrast, CL2 alpha and CL2 beta contained a full N-terminal Dx, whereas CLr only possessed a partial and dysfunctional Dx. Interestingly, despite a large similarity in the kinase domain, CL1/CL2/CLr had an impact on CRE-dependent gene expression distinct from that of the related CaMKI/CaMKIV and CaMKII. Although these were previously shown to activate Ca2+/cAMP-response element-binding protein (CREB)-dependent transcription, we here show that CL1 and CL2 were unable to significantly phosphorylate CREB Ser-133 and rather inhibited CRE-dependent gene expression by a dominant mechanism that bypassed CREB and was mediated by phosphorylated TORC2.