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Myristoylated Alanine-Rich C-Kinase Substrate Protein*: A Major Intracellular Regulatory Molecule Controlling Secretion of Mucin by Human Airway Goblet Cells

Kenneth B. Adler, PhD; Y. Li, PhD; L. D. Martin, PhD
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*From the North Carolina State University, Raleigh, NC.

Correspondence to: Kenneth B. Adler, PhD, North Carolina State University, College of Veterinary Medicine, 4700 Hillsborough St, Raleigh, NC 27606



Chest. 2000;117(5_suppl_1):266S-267S. doi:10.1378/chest.117.5_suppl_1.266S
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Abbreviations: cGMP = cyclic guanosine monophosphate; MARCKS = myristoylated alanine-rich C-kinase substrate; mRNA = messenger RNA; PMA = phorbol ester.

Hypersecretion of mucus contributes to airway inflammation and obstruction in COPD. Despite identification of numerous secretagogues, common signaling pathways and intracellular molecules involved in mucin secretion have not been elucidated. Here, we present evidence that myristoylated alanine-rich C-kinase substrate (MARCKS) protein, a major cellular substrate for protein kinase C, is a central, convergent intracel-lular molecule controlling release of mucin granules by airway goblet cells. The mechanism appears to involve secretagogue-stimulated activation of protein kinase C, which leads to MARCKS phosphorylation and detachment from plasma membrane into the cytosol. This is followed by activation of cyclic guanosine monophosphate (cGMP) -dependent protein kinases, which in turn activate a cytosolic phosphatase, dephosphorylating MARCKS and allowing it to attach to mucin granule membranes, whereby it mediates granule release via interactions with cytoskeletal components. We have identified, for the first time, MARCKS messenger RNA (mRNA) and protein in human bronchial epithelial cells, and both mRNA and protein levels increased with secretory cell differentiation when these cells were maintained in air/liquid interface culture. MARCKS in these cells was phosphorylated by the phorbol ester, PMA, while subsequent addition of the cGMP activator, 8 bromo-cGMP, caused dephosphorylation. Mucin hypersecretion provoked by the pathophysiologically relevant secretagogue, uridine triphosphate, or by a combination of PMA + 8 bromo-cGMP, was inhibited in a concentration-dependent manner by a synthetic peptide with a sequence identical to the myristic acid containing N-terminal region of MARCKS protein, the site of its attachment to granule membranes. An antisense oligonucleotide directed against MARCKS also blocked mucin secretion. Relatedly, the PKC inhibitor, calphostin C; the cGMP inhibitor, Rp-8-Br-PET-cGMP; or the phosphatase inhibitor, okadaic acid, independently inhibited mucin secretion provoked by the above secretagogues. The results indicate that MARCKS protein plays a major role in mediating human airway mucin secretion.

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