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Blood, 1 August 2005, Vol. 106, No. 3, pp. 1076-1083.
Prepublished online as a Blood First Edition Paper on April 19, 2005; DOI 10.1182/blood-2004-09-3755.
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Submitted September 28, 2004
Accepted March 10, 2005
Characterization of the role of CamKI Like Kinase (CKLiK) in human granulocyte function
Sandra Verploegen, Laurien Ulfman, Hanneke van Deutekom, Corneli van Aalst, Henk Honing, Jan-Willem J Lammers, Leo Koenderman, and Paul J Coffer*
Dept. of Pulmonary Diseases, University Medical Center, Utrecht, The Netherlands
* Corresponding author; email: p.coffer{at}azu.nl.
Activation of granulocyte effector functions, such as induction of the respiratory burst and migration, are regulated by a variety of relatively ill-defined signaling pathways. Recently we identified a novel Ca2+/calmodulin dependent protein kinase CKLiK, which exhibits restricted mRNA expression to human granulocytes. Utilizing a novel antibody generated against the C-terminus of CKLiK, CKLiK was detected in CD34+ derived neutrophils and eosinophils, as well as in mature peripheral blood granulocytes. Activation of human granulocytes by N-formyl-methionyl-leucyl-phenylalanine (fMLP) and Platelet Activating Factor (PAF), but not the phorbol ester PMA, resulted in induction of CKLiK activity, in parallel with a rise of intracellular Ca2+ [Ca2+]i. In order to study the functionality of CKLiK in human granulocytes, a cell permeable CKLiK peptide inhibitor (CKLiK297-321) was generated which was able to inhibit kinase activity in a dose-dependent manner. The effect of this peptide was studied on specific granulocyte effector functions such as phagocytosis, respiratory burst, migration and adhesion. Phagocytosis of Aspergillus fumigatus particles was reduced in the presence of CKLiK (297-321) and fMLP-induced ROS production was potently inhibited by CKLiK(297-321) in a dose dependent manner. Furthermore, fMLP-induced neutrophil migration on albumin coated surfaces was perturbed, as well as  2-integrin mediated adhesion. These findings suggest a critical role for CKLiK in modulating chemoattractant induced functional responses in human granulocytes.
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