Survival signaling in type II pneumocytes activated by surfactant protein-A.
Surfactant-associated protein-A (SP-A) is a component of pulmonary surfactant that acts as a cytokine through interaction with a cell-surface receptor (SPAR) on lung epithelial cells. SP-A regulates important physiological processes including surfactant secretion, gene expression, and protection against apoptosis. Tyrosine kinase and PI3K inhibitors block effects of SP-A, suggesting that SPAR may be a receptor tyrosine kinase and activate the PI3K-PKB/Akt pathway. Here we report that SP-A treatment leads to rapid tyrosine-specific phosphorylation of several important proteins in lung epithelial cells including insulin receptor substrate-1 (IRS-1), an upstream activator of PI3K. Analysis of anti-apoptotic signaling species downstream of IRS-1 showed activation of PKB/Akt but not of MAPK. Phosphorylation of IkappaB was minimally affected by SP-A as was NFkappaB gel shift activity. However, FKHR was rapidly phosphorylated in response to SP-A and its DNA-binding activity was significantly reduced. Since FKHR is pro-apoptotic, this may play an important role in signaling the anti-apoptotic effects of SP-A. Therefore, we have characterized survival-enhancing signaling activated by SP-A leading from SPAR through IRS-1, PI3K, PKB/Akt, and FKHR. The activity of this pathway may explain, in part, the resilience of type II cells to lung injury and their survival to repopulate alveolar epithelium after peripheral lung damage.
White
Martyn K
MK
Department of Pathology, anatomy, and cell Biology, Jefferson medical College, Tomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA. Martyn.White@mail.tju.edu
Strayer
David S
DS
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002417:Cattle; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D055504:Insulin Receptor Substrate Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011650:Pulmonary Alveoli / Q000166:cytology* / Q000378:metabolism; D037662:Pulmonary Surfactant-Associated Protein A / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; C494821:Bad protein, rat; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D020672:I-kappa B Proteins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009419:Nerve Tissue Proteins; C000606206:Nfkbia protein, rat; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D037662:Pulmonary Surfactant-Associated Protein A; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; C067774:surfactant protein A receptor; D000072000:NF-KappaB Inhibitor alpha; C074639:Foxo1 protein, rat; D014443:Tyrosine; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases