Protein kinase C delta regulates airway mucin secretion via phosphorylation of MARCKS protein.
Mucin hypersecretion is a major pathological feature of many respiratory diseases, yet cellular mechanisms regulating secretion of mucin have not been fully elucidated. Previously, we reported that mucin hypersecretion induced by human neutrophil elastase involves activation of protein kinase C (PKC), specifically the delta-isoform (PKC delta). Here, we further investigated the role of PKC delta in mucin hypersecretion using both primary human bronchial epithelial cells and the human bronchial epithelial 1 cell line as in vitro model systems. Phorbol-12-myristate-13-acetate (PMA)-induced mucin hypersecretion was significantly attenuated by rottlerin, a PKC delta-selective inhibitor. Rottlerin also reduced PMA- or human neutrophil elastase-induced phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) protein in these cells. Both secretion and MARCKS phosphorylation were significantly enhanced by the PKC delta activator bryostatin 1. A dominant-negative PKC delta construct (pEGFP-N1/PKC delta K376R) transfected into human bronchial epithelial 1 cells significantly attenuated both PMA-induced mucin secretion and phosphorylation of MARCKS, whereas transfection of a wild-type construct increased PKC delta and enhanced mucin secretion and MARCKS phosphorylation. Similar transfections of a dominant-negative or wild-type PKC epsilon construct did not affect either mucin secretion or MARCKS phosphorylation. The results suggest that PKC delta plays an important role in mucin secretion by airway epithelium via regulation of MARCKS phosphorylation.
Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St., Raleigh, NC 27606, USA.
Jin-Ah
JA
Park
Anne L
AL
Crews
William R
WR
Lampe
Shijing
S
Fang
Joungjoa
J
Park
Kenneth B
KB
Adler
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D054713:Bryostatins / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009077:Mucins / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000098:Acetophenones; D001578:Benzopyrans; D054713:Bryostatins; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; D008565:Membrane Proteins; D009077:Mucins; D047428:Protein Kinase Inhibitors; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C046785:bryostatin 1; C085746:rottlerin; D051745:Protein Kinase C-delta; D013755:Tetradecanoylphorbol Acetate