Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The regulation of the multifunctional calcium/calmodulin dependent protein kinase II (CaMKII) by serine/threonine protein phosphatases has been extensively studied in neuronal cells; however, this regulation has not been investigated previously in fibroblasts. We cloned a cDNA from SV40-transformed human fibroblasts that shares 80% homology to a rat calcium/calmodulin-dependent protein kinase phosphatase that encodes a PPM1F protein. By using extracts from transfected cells, PPM1F, but not a mutant (R326A) in the conserved catalytic domain, was found to dephosphorylate in vitro a peptide corresponding to the auto-inhibitory region of CaMKII. Further analyses demonstrated that PPM1F specifically dephosphorylates the phospho-Thr-286 in autophosphorylated CaMKII substrate and thus deactivates the CaMKII in vitro. Coimmunoprecipitation of CaMKII with PPM1F indicates that the two proteins can interact intracellularly. Binding of PPM1F to CaMKII involves multiple regions and is not dependent on intact phosphatase activity. Furthermore, overexpression of PPM1F in fibroblasts caused a reduction in the CaMKII-specific phosphorylation of the known substrate vimentin(Ser-82) following induction of the endogenous CaM kinase. These results identify PPM1F as a CaM kinase phosphatase within fibroblasts, although it may have additional functions intracellularly since it has been presented elsewhere as POPX2 and hFEM-2. We conclude that PPM1F, possibly together with the other previously described protein phosphatases PP1 and PP2A, can regulate the activity of CaMKII. Moreover, because PPM1F dephosphorylates the critical autophosphorylation site of CaMKII, we propose that this phosphatase plays a key role in the regulation of the kinase intracellularly.
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PMID:Regulation of the multifunctional Ca2+/calmodulin-dependent protein kinase II by the PP2C phosphatase PPM1F in fibroblasts. 1514 Aug 79

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP/PPM1F) is a Ser/Thr protein phosphatase that dephosphorylates and regulates multifunctional Ca(2+)/calmodulin-dependent protein kinases. Although CaMKP is known to be activated by phosphorylation with CaMKII and stimulated by the addition of polycations such as poly-l-lysine, detailed mechanisms of regulation of CaMKP in vivo still remain unclear. In the present study, we found that CaMKP is regulated by oxidation/reduction at Cys residue(s). When CaMKP was incubated with H(2)O(2), time- and dose-dependent inactivation of the enzyme was observed. This inactivation was restored when the inactivated CaMKP was treated with a reducing agent such as 2-mercaptoethanol. Since there are three Cys residues (Cys-259, Cys-315, and Cys-359) in human CaMKP (hCaMKP), we produced three point mutants of hCaMKP, CaMKP(C259S), CaMKP(C315S), and CaMKP(C359S), of which the Cys residues were replaced by Ser residues. Among these Cys-substituted mutants, only CaMKP(C359S) exhibited significant tolerance against oxidation by H(2)O(2). Incubation of CaMKP with H(2)O(2) led to formation of disulfide bond between Cys-359 and Cys-259/Cys-315, resulting in the inactivation of the enzyme. These results suggest that hCaMKP activity is reversibly regulated by oxidation/reduction at Cys-359.
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PMID:Regulation of Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) by oxidation/reduction at Cys-359. 2274 49