ABSTRACT
Mucus is a viscoelastic, gel-like substance produced and secreted by epithelium and submucosal glands in the mammalian respiratory, gastrointestinal, and reproductive tracts. It coats the epithelial surfaces to serve as a selective physical barrier between the extracellular milieu and the epithelial cell layer. Mucus consists of water, ions, mucin glycoproteins (mucins), and other secreted proteins including immunoglobulins; among them mucin is the major structural component and the basis for the viscous and gel-like property of mucus. In mammalian airways, the mucus layer serves as the first line of defense against inhaled pollutants and pathogens by trapping these foreign substances and clearing them out of airways via the mucociliary apparatus. Excess secretion of mucus can have deleterious effects on airways. It can lead to clogging of airways, compromising exchange of gases, increasing microbial infection, and even inducing severe inflammatory responses to cause destruction of airway walls and contiguous tissues. It has long been known that, in airway diseases such as asthma, chronic bronchitis, and cystic 179
fibrosis, hypersecretion of mucus is a common lesion. Despite the obvious pathophysiological importance, mechanisms controlling secretion of airway mucin have not been elucidated. MUCIN SECRETION
In order to understand the mechanisms controlling mucin secretion, a great deal of related research in the last two decades has focused on identifying mucin secretagogues and their corresponding signaling pathways in different species and model systems. As a result, a wide variety of agents and inflammatory/humoral mediators have been found capable of provoking mucin hypersecretion, including cholinergic agonists (1), lipid mediators (2,3), oxidants (3,4), cytokines (5), neuropeptides (6), purinergic agonists such as ATP and UTP (7-10), bacterial products (11), elastase (12), and inhaled pollutants (13,14). Interestingly, most of these secretagogues also are known as activators of protein kinases, especially protein kinase C (PKC) and cGMP-dependent protein kinase (protein kinase G, or PKG). Indeed, it has been found recurrently by many research groups that a variety of secretagogues induce mucin secretion via PKC or the nitric oxide (NO)- cGMP-PKG pathway (4,7-10,15-19). These findings have been remarkably consistent regardless of different experimental techniques and different species or model systems used. Given the apparent connection between mucin secretion and protein kinase activation elicited by various secretagogues, it appears that there could exist a universal signaling mechanism controlling mucin secretion, in which cellular substrates of either PKC and/or PKG could be pivotal, convergent molecules linking protein kinase activation to movement of mucin granules out of cells.Recently, we have amassed evidence that MARCKS protein (myristoylated alanine-rich C kinase substrate) may be such a molecule. MARCKS is a substrate for PKC and is phosphorylated by activated PKC. Here we provide a review of MARCKS protein and a rationale for looking at MARCKS protein as a potentially important regulator of airway mucin secretion. MARCKS PROTEIN
Myristoylated alanine-rich C kinase substrate, or MARCKS protein, is a widely distributed, specific cellular substrate for PKC. It is a myristoylated, membrane-associated protein, and also contains sites for calmodulin and actin filament binding. While the definitive functional role(s) of MARCKS is/are not yet clear, it has been implicated in a variety of biological processes that require actin cytoskeleton involvement, including cell motility, secretion, membrane trafficking, proliferation, and transformation (20-23).
