title: PKG-1α mediates GATA4 transcriptional activity.
abstract: GATA4, a zinc-finger transcription factor, is central for cardiac development and diseases. Here we show that GATA4 transcriptional activity is mediated by cell signaling via cGMP dependent PKG-1α activity. Protein kinase G (PKG), a serine/tyrosine specific kinase is the major effector of cGMP signaling. We observed enhanced transcriptional activity elicited by co-expressed GATA4 and PKG-1α. Phosphorylation of GATA4 by PKG-1α was detected on serine 261 (S261), while the C-terminal activation domain of GATA4 associated with PKG-1α. GATA4's DNA binding activity was enhanced by PKG-1α via by both phosphorylation and physical association. More importantly, a number of human disease-linked GATA4 mutants exhibited impaired S261 phosphorylation, pointing to defective S261 phosphorylation in the elaboration of human heart diseases. We showed S261 phosphorylation was favored by PKG-1α but not by PKA, and several other kinase signaling pathways such as MAPK and PKC. Our observations demonstrate that cGMP-PKG signaling mediates transcriptional activity of GATA4 and links defective GATA4 and PKG-1α mutations to the development of human heart disease.
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, Guangdong 510515, China; Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan 570102, China; The Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, TX 77030, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, Guangdong 510515, China. Electronic address: yuyh1010@hotmail.com.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA; Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. Electronic address: rjschwartz@uh.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
mesh_terms: D009320:Atrial Natriuretic Factor / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D009320:Atrial Natriuretic Factor; D004247:DNA; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D006152:Cyclic GMP
keywords: GATA4; NPPA; PKG-1α; Phosphorylation; cGMP