title: Hepatocyte growth factor suppresses proinflammatory NFkappaB activation through GSK3beta inactivation in renal tubular epithelial cells.
abstract: Activation of NFkappaB is a fundamental cellular event central to all inflammatory diseases. Hepatocyte growth factor (HGF) ameliorates both acute and chronic inflammation in a multitude of organ systems through modulating NFkappaB activity; nevertheless, the exact molecular mechanism remains uncertain. Here we report that HGF through inactivation of GSK3beta suppresses NFkappaB p65 phosphorylation specifically at position Ser-468. The Ser-468 of RelA/p65 situates in a GSK3beta consensus motif and could be directly phosphorylated by GSK3beta both in vivo and in vitro, signifying Ser-468 of RelA/p65 as a putative substrate for GSK3beta. In addition, the C terminus of RelA/p65 harbors a highly conserved domain homologue of the consensus docking sequence for GSK3beta. Moreover, this domain was required for efficient phosphorylation of Ser-468 and was indispensable for the physical interaction between RelA/p65 and GSK3beta. HGF substantially intercepted this interaction by inactivating GSK3beta. Functionally, phosphorylation of Ser-468 of RelA/p65 was required for the induced expression of a particular subset of proinflammatory NFkappaB-dependent genes. Diminished phosphorylation at Ser-468 by HGF resulted in a gene-specific inhibition of these genes' expression. The action of HGF on proinflammatory NFkappaB activation was consistently mimicked by a selective GSK3beta inhibitor or GSK3beta knockdown by RNA interference but largely abrogated in cells expressing the mutant uninhibitable GSK3beta. Collectively, our findings suggest that HGF has a potent suppressive effect on NFkappaB activation, which is mediated by GSK3beta, an important signaling transducer controlling RelA/p65 phosphorylation specificity and directing the transcription of selective proinflammatory cytokines implicated in inflammatory kidney disease.
authors.affiliation: Division of Kidney Disease and Hypertension, Department of Medicine, Brown University School of Medicine, Provindence, Rhode Island 02903, USA. Rujun_Gong@Brown.edu
authors.forename: Rujun
authors.initials: R
authors.lastname: Gong
authors.forename: Abdalla
authors.initials: A
authors.lastname: Rifai
authors.forename: Yan
authors.initials: Y
authors.lastname: Ge
authors.forename: Shan
authors.initials: S
authors.lastname: Chen
authors.forename: Lance D
authors.initials: LD
authors.lastname: Dworkin
mesh_terms: D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D017228:Hepatocyte Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3