PT - JOURNAL ARTICLE AU - Allen Sam Titus AU - V Harikrishnan AU - Shivakumar Kailasam TI - Identification of a common regulatory pathway that determines cell survival and cell cycle progression in cardiac fibroblasts AID - 10.1101/857037 DP - 2019 Jan 01 TA - bioRxiv PG - 857037 4099 - http://biorxiv.org/content/early/2019/11/27/857037.short 4100 - http://biorxiv.org/content/early/2019/11/27/857037.full AB - Relative resistance to apoptosis and the ability to proliferate and produce a collagen-rich scar determine the critical role of cardiac fibroblasts in wound healing and tissue remodeling following myocardial injury. Identification of cardiac fibroblast-specific factors and mechanisms underlying these aspects of cardiac fibroblast function is therefore of considerable scientific and clinical interest. In the present study, gene knockdown and over-expression approaches, and promoter binding assays, showed that DDR2, a mesenchymal cell-specific collagen receptor tyrosine kinase localized predominantly in fibroblasts in the heart, acts via ERK1/2 MAPK-activated SRF transcription factor to enhance the expression of anti-apoptotic cIAP2 in cardiac fibroblasts, conferring resistance against oxidative injury. Further, DDR2 was found to act via ERK1/2 MAPK-activated SRF to transcriptionally up-regulate Skp2 that in turn facilitated post-translational degradation of p27, the cyclin-dependent kinase inhibitor that causes cell cycle arrest, to promote G1-S transition, as evidenced by Rb phosphorylation, increased PCNA levels and flow cytometry. DDR2-dependent ERK1/2 MAPK activation also suppressed FoxO3a-mediated transcriptional induction of p27. Notably, DDR2 levels positively correlated with SRF, cIAP2 and PCNA levels in cardiac fibroblasts from Spontaneously Hypertensive Rats. To conclude, DDR2-mediated ERK1/2 MAPK activation facilitates coordinated regulation of cell survival and cell cycle progression in cardiac fibroblasts via SRF.DDR2Discoidin Domain Receptor 2SRFSerum Response FactorERK1/2 MAPKExtracellular signal-regulated kinase1/2 Mitogen-activated Protein KinasecIAP2Cellular inhibitors of apoptosis protein 2FoxO3abox O 3a transcription factorSkp2S-Phase Kinase Associated Protein 2MAPKMitogen-Activated Protein Kinase