Regulation and function of the calcium/calmodulin-dependent protein kinase IV/protein serine/threonine phosphatase 2A signaling complex

被引:53
作者
Anderson, KA
Noeldner, PK
Reece, K
Wadzinski, BE
Means, AR [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
[2] Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37232 USA
关键词
D O I
10.1074/jbc.M404523200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Calcium/calmodulin-dependent protein kinase IV (CaMKIV) is a member of the broad substrate specificity class of Ca2+/calmodulin (CaM)-dependent protein kinases and functions as a potent stimulator of Ca2+-dependent gene expression. Activation of CaMKIV is a transient, tightly regulated event requiring both Ca2+/ CaM binding and phosphorylation of the kinase on T200 by an upstream CaMK kinase ( CaMKK). Previously, CaMKIV was shown to stably associate with protein serine/ threonine phosphatase 2A (PP2A), which was proposed to play a role in negatively regulating the kinase. Here we report that the Ca2+/CaM binding-autoinhibitory domain of CaMKIV is required for association of the kinase with PP2A and that binding of PP2A and Ca2+/ CaM appears to be mutually exclusive. We demonstrate that inhibition of the CaMKIV/PP2A association in cells results in enhanced CaMKIV-mediated gene transcription that is independent of Ca2+/CaM. The enhanced transcriptional activity correlates with the elevated level of phospho-T200 that accumulates when CaMKIV is prevented from interacting with PP2A. Collectively, these data suggest a molecular basis for the sequential activation and inactivation of CaMKIV. First, in response to an increase in intracellular Ca2+, CaMKIV binds Ca2+/CaM and becomes phosphorylated on T200 by CaMKK. These events result in the generation of autonomous activity required for CaMKIV-mediated transcriptional regulation. The CaMKIV-associated PP2A then dephosphorylates CaMKIV T200, thereby terminating autonomous activity and CaMKIV-mediated gene transcription.
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页码:31708 / 31716
页数:9
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