title: Surfactant protein A regulates pulmonary surfactant secretion via activation of phosphatidylinositol 3-kinase in type II alveolar cells.
abstract: Pulmonary surfactant is secreted by the type II alveolar cells of the lung, and this secretion is induced by secretagogues of several types (e.g., ionomycin, phorbol esters, and terbutaline). Secretagogue-induced secretion is inhibited by surfactant-associated protein A (SP-A), which binds to a specific receptor (SPAR) on the surface of type II cells. The mechanism of SP-A-activated SPAR signaling is completely unknown. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 rescued surfactant secretion from inhibition by SP-A. In order to directly demonstrate a role for PI3K in SPAR signaling, PI3K activity was immunoprecipitated from type II cell extracts. PI3K activity increased rapidly after SP-A addition to type II cells. Since many receptors that activate PI3K do so through tyrosine-specific protein phosphorylation, antisera to phosphotyrosine, insulin-receptor substrate-1 (IRS-1), or SPAR were also examined. These antisera coimmunoprecipitated PI3K activity that was stimulated by SP-A. In addition, the tyrosine-specific protein kinase inhibitors genistein and herbimycin A blocked the action of SP-A on surfactant secretion. We conclude that SP-A signals to regulate surfactant secretion through SPAR, via pathways that involve tyrosine phosphorylation, include IRS-1, and entail activation of PI3K. This activation leads to inhibition of secretagogue-induced secretion of pulmonary surfactant.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA. Martyn.White@mail.tju.edu
authors.forename: M K
authors.initials: MK
authors.lastname: White
authors.forename: D S
authors.initials: DS
authors.lastname: Strayer
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D019319:Okadaic Acid / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011510:Proteolipids / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000378:metabolism*; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D014443:Tyrosine / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019833:Genistein; D055504:Insulin Receptor Substrate Proteins; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019319:Okadaic Acid; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D011510:Proteolipids; D037662:Pulmonary Surfactant-Associated Protein A; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D011809:Quinones; D011956:Receptors, Cell Surface; D017828:Rifabutin; D014443:Tyrosine; C526296:Irs1 protein, rat; C067774:surfactant protein A receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C020754:herbimycin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one