The fibroblast, a cell central to effective wound remodeling, not only contains various growth factor receptors but also high activities of a guanylyl cyclase receptor (GC-B). Here we demonstrate that marked elevations of cyclic GMP induced by C-type natriuretic peptide (CNP), the ligand of GC-B, blocks activation of the mitogen-activated protein kinase cascade in fibroblasts. We also show that platelet-derived growth factor, fibroblast growth factor, serum, or Na 3 VO 4 rapidly (within 5 min) and extensively (up to 85% inhibition) disrupt CNP-dependent elevations of cyclic GMP. In addition, the mitogens also lower cyclic GMP concentrations (50% decrease) in cells not treated with CNP. Cytoplasmic forms of guanylyl cyclase, in contrast to the CNP-stimulated pathway, are not antagonized by the various mitogens. The effects of the mitogens on cellular cyclic GMP are fully explained by a direct and stable inactivation of GC-B. Homogenates obtained from fibroblasts treated with or without the various mitogens contain equivalent amounts of GC-B protein, but both ligand-dependent and ligand-independent activity are markedly (up to 90% inhibition of CNP-dependent activity) decreased after mitogen addition. The stable inactivation is correlated with the dephosphorylation of phosphoserine and phosphothreonine residues of the cyclase receptor. These results not only establish a specific and reciprocal antagonistic relationship between mitogen-activated and GC-Bregulated signaling pathways in the fibroblast but also suggest that one of the earliest events following mitogen activation of a fibroblast is an interruption of cyclic GMP production from this receptor.Wound healing and tissue remodeling require exquisite spatial and temporal coordination of chemotactic, proliferative, and secretory responses in multiple cells (1). The fibroblast, a cell central to the above processes, is tightly regulated by a host of growth and chemotactic factors that govern its migration, proliferation, and extracellular matrix remodeling (2, 3). A number of years ago we demonstrated that fibroblast cell lines contain particularly high activities of a guanylyl cyclase receptor, GC-B, 1 that binds C-type natriuretic peptide (CNP) with high affinity (4). CNP, the most highly conserved of the natriuretic peptides (5, 6), is synthesized in various regions throughout the body including endothelial cells but is not found in appreciable quantities in blood, suggesting it acts in an autocrine or paracrine manner. Aside from GC-B, some fibroblast cell lines also appear to contain a soluble form of guanylyl cyclase responsive to nitric oxide (7, 8) and low activities of GC-A, the atrial natriuretic peptide receptor (4). Substantial evidence exists that cyclic GMP is an antagonist of mitogen action in many cell types. Whether elevated by stimulation of cell-surface receptor-linked guanylyl cyclases, by stimulation of cytosolic guanylyl cyclases, or by direct addition of cell-permeant analogs, cyclic GMP slows the onset of DNA synthesis, decreases cell pr...

Recent studies have demonstrated key roles for several membrane guanylyl cyclase receptors in the regulation of cell hyperplasia, hypertrophy, migration and extracellular matrix production, all of which having an impact on clinically relevant diseases, including tissue remodeling after injury. Additionally, cell differentiation, and even tumor progression, can be profoundly influenced by one or more of these receptors. Some of these receptors also mediate important communication between the heart and intestine, and the kidney to regulate blood volume and Na + balance.

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