title: CaMKII protects MKP-1 from proteasome degradation in endothelial cells.
abstract: CaMKs are a widely distributed family of kinases with multiple and often cell specific effects on intracellular signal transduction pathway. In endothelial cells, it has been recognized a role for CamKII in several pathways such as eNOS activation and nitric oxide production. It is not clear though, whether CaMKII interfere with other endothelial cell functions such as ERK activation and cell proliferation. We explored this issue in primary cultured rat endothelial cells and we evaluated the effect on endothelial cell proliferation and DNA synthesis. CaMKII inhibition through Cantide, conducted into the cell through Antoennapedia (ANT-CN), showed positive effects on proliferation and H(3)-thimdine incorporation similar to insulin stimulation. Accordingly, both CaMKII pharmacological inhibition and silencing through shRNA produced activation of the p44/42 MAPK. These observations leaded to the hypothesis that CamKII could regulate p44/p42 by interfering with specific ERK phosphatases. Indeed, we found that CaMKII interacts and protect the dual specific phosphatase MKP-1 from proteasome mediated degradation while this complex is disrupted by CaMKII inhibitors. This study reveals that CaMKII, besides phosphorylation through the known ras-raf-mek pathway, can regulate also dephosphorylation of p44/p42 by modulation of MKP-1 level. This novel finding opens to a novel scenario in regulation of endothelial cell functions.
authors.affiliation: Department of Medicine, University of Salerno, Italy. Electronic address: mciccarelli@unisa.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Ciccarelli
authors.affiliation: Department of Translational Science, "Federico II" University of Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Rusciano
authors.affiliation: Department of Advanced Biomedical Science, "Federico II" University of Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sorriento
authors.affiliation: Department of Advanced Biomedical Science, "Federico II" University of Naples, Italy.
authors.forename: Maria Felicia
authors.initials: MF
authors.lastname: Basilicata
authors.affiliation: Department of Advanced Biomedical Science, "Federico II" University of Naples, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Pharmacology, University of Salerno, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Department of Pharmacology, University of Salerno, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bertamino
authors.affiliation: Department of Translational Science, "Federico II" University of Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Luca
authors.affiliation: Department of Advanced Biomedical Science, "Federico II" University of Naples, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.affiliation: Department of Medicine, University of Salerno, Italy; IRCCS "Multimedica", Milan, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.affiliation: Department of Translational Science, "Federico II" University of Naples, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Illario
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D054638:Dual Specificity Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008387:Marine Toxins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D054735:Phosphorothioate Oligonucleotides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D007976:Leupeptins; D008387:Marine Toxins; D010080:Oxazoles; D054735:Phosphorothioate Oligonucleotides; C478563:cantide; C059041:calyculin A; D004247:DNA; D019908:Proto-Oncogene Proteins c-raf; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: CaMKII; Endothelial Cell; Phosphatases