Protein kinase A regulates beta2 integrin avidity in neutrophils.
The adhesive phenotype of neutrophils (PMN) depends largely on activating and deactivating intracellular signals regulating beta2 integrin avidity for ligand. Our hypothesis is that PKA is a negative regulator of beta2 integrin avidity. In this work, we examined the role of PKA in PMN alphaMbeta2 integrin activation. Elevation of cAMP inhibited alphaMbeta2 integrin-dependent adhesion of PMN to immune complexes (IC), but not PMA-induced adhesion. The PKA inhibitor KT5720 reversed the ability of cAMP to suppress adhesion to IC. Moreover, inhibition of PKA activity was sufficient to activate alphaMbeta2 integrin-dependent adhesion and increase beta2 integrin expression and binding of the monoclonal antibody CBRM1/5, which recognizes activated alphaMbeta2 specifically. However, PKA activity was necessary for sustained adhesion. Disruption of A kinase-anchoring, protein-PKA binding with a cell-permeant peptide derived from the AKAP Ht31 also activated adhesion. Unlike pharmacologic inhibition of PKA, AKAP peptide-induced adhesion was PKC dependent and did not affect beta2 integrin expression or CBRM1/5 binding. These data demonstrate that PKA appears to have a dual role in the mechanism regulating alphaMbeta2 integrin avidity and adhesion.
Jones
Samuel L
SL
Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606, USA. sam_jones@ncsu.edu
D018821:CD18 Antigens / Q000097:blood*; D002227:Carbazoles; D002448:Cell Adhesion; D000242:Cyclic AMP / Q000097:blood; D017868:Cyclic AMP-Dependent Protein Kinases / Q000097:blood*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008024:Ligands; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D013449:Sulfonamides
D018821:CD18 Antigens; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D007546:Isoquinolines; D008024:Ligands; D011758:Pyrroles; D013449:Sulfonamides; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide