Protein kinase Cν/protein kinase D3 nuclear localization, catalytic activation, and intracellular redistribution in response to G protein-coupled receptor agonists
Protein kinase Cν/protein kinase D3 nuclear localization, catalytic activation, and intracellular redistribution in response to G protein-coupled receptor agonists
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DOI：
10.1074/jbc.m300226200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Rozengurt, E
中科院分区：
文献类型：
--
作者：
Rey, O;Yuan, JZ;Rozengurt, E
蛋白激酶D（PKD）家族由三种丝氨酸/苏氨酸激酶组成：PKCmu/PKD、PKD 2和PKCnu/PKD 3。虽然PKD一直是大多数研究的焦点，但实际上对G蛋白偶联受体激动剂（GPCR）对PKD 3的调节特性和细胞内分布的影响一无所知。因此，我们研究了介导其激活和细胞内分布的机制。GPCR激动剂通过蛋白激酶C（PKC）依赖性途径诱导PKD 3的快速活化，该途径导致PKD 3的活化环的磷酸化。内源性或标记的PKD 3与PKD和PKD 2在未刺激的细胞中的稳态分布的比较表明，而PKD和PKD 2主要是细胞质，PKD 3存在于细胞核和细胞质中。PKD 3的这种分布是由于其通过需要核输入受体和胜任的CRM 1-核输出途径的机制在两个隔室之间连续穿梭。细胞刺激GPCR激动剂神经降压素诱导的快速和可逆的PKC依赖的PKD 3的质膜易位。有趣的是，PKD 3的核积累可以响应其激活而显著增强。因此，这项研究表明，PKD同工酶的细胞内分布是不同的，并建议他们的信号转导特性的差异定位调节。
The protein kinase D (PKD) family consists of three serine/threonine kinases: PKCmu/PKD, PKD2, and PKCnu/PKD3. Whereas PKD has been the focus of most studies, virtually nothing is known about the effect of G protein-coupled receptor agonists ( GPCR) on the regulatory properties and intracellular distribution of PKD3. Consequently, we examined the mechanism that mediates its activation and intracellular distribution. GPCR agonists induced a rapid activation of PKD3 by a protein kinase C (PKC)-dependent pathway that leads to the phosphorylation of the activation loop of PKD3. Comparison of the steady-state distribution of endogenous or tagged PKD3 versus PKD and PKD2 in unstimulated cells indicated that whereas PKD and PKD2 are predominantly cytoplasmic, PKD3 is present both in the nucleus and cytoplasm. This distribution of PKD3 results from its continuous shuttling between both compartments by a mechanism that requires a nuclear import receptor and a competent CRM1-nuclear export pathway. Cell stimulation with the GPCR agonist neurotensin induced a rapid and reversible plasma membrane translocation of PKD3 that is PKC-dependent. Interestingly, the nuclear accumulation of PKD3 can be dramatically enhanced in response to its activation. Thus, this study demonstrates that the intracellular distribution of PKD isoenzymes are distinct, and suggests that their signaling properties are regulated by differential localization.