PMID- 25267645 OWN - NLM STAT- MEDLINE DCOM- 20150430 LR - 20211021 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 111 IP - 41 DP - 2014 Oct 14 TI - IKK phosphorylates RelB to modulate its promoter specificity and promote fibroblast migration downstream of TNF receptors. PG - 14794-9 LID - 10.1073/pnas.1410124111 [doi] AB - TNFalpha is a potent cytokine that plays a critical role in numerous cellular processes, particularly immune and inflammatory responses, programmed cell death, angiogenesis, and cell migration. Thus, understanding the molecular mechanisms that mediate TNFalpha-induced cellular responses is a crucial issue. It is generally accepted that global DNA binding activity of the NF-kappaB avian reticuloendotheliosis viral (v-rel) oncogene related B (RelB) subunit is not induced upon TNFalpha treatment in fibroblasts, despite its TNFalpha-induced nuclear accumulation. Here, we demonstrate that RelB plays a critical role in promoting fibroblast migration upon prolonged TNFalpha treatment. We identified the two kinases IkappaB kinase alpha (IKKalpha) and IkappaB kinase beta (IKKbeta) as RelB interacting partners whose activation by TNFalpha promotes RelB phosphorylation at serine 472. Once phosphorylated on serine 472, nuclear RelB dissociates from its interaction with the inhibitory protein IkappaBalpha and binds to the promoter of critical migration-associated genes, such as the matrix metallopeptidase 3 (MMP3). Further, we show that RelB serine 472 phosphorylation status controls MMP3 expression and promigration activity downstream of TNF receptors. Our findings provide new insights into the regulation of RelB activity and reveal a novel link between selective NF-kappaB target gene expression and cellular response in response to TNFalpha. FAU - Authier, Helene AU - Authier H AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Billot, Katy AU - Billot K AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Derudder, Emmanuel AU - Derudder E AD - Immune Regulation and Cancer, Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. FAU - Bordereaux, Didier AU - Bordereaux D AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Riviere, Pierre AU - Riviere P AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Rodrigues-Ferreira, Sylvie AU - Rodrigues-Ferreira S AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Nahmias, Clara AU - Nahmias C AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and. FAU - Baud, Veronique AU - Baud V AD - Institut National de la Sante et de la Recherche Medicale, U1016, Institut Cochin, 75014 Paris, France; Centre National de la Recherche Scientifique, Unite Mixte de Recherche 8104, 75014 Paris, France; Universite Paris Descartes, Sorbonne Paris Cite, 75014 Paris, France; and veronique.baud@inserm.fr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140929 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (I-kappa B Proteins) RN - 0 (NFKBIA protein, human) RN - 0 (Nfkbia protein, mouse) RN - 0 (Receptors, Tumor Necrosis Factor) RN - 0 (Tumor Necrosis Factor-alpha) RN - 139874-52-5 (NF-KappaB Inhibitor alpha) RN - 147337-75-5 (Transcription Factor RelB) RN - 17885-08-4 (Phosphoserine) RN - EC 2.7.11.10 (I-kappa B Kinase) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Animals MH - *Cell Movement/drug effects MH - Cell Nucleus/drug effects/metabolism MH - Fibroblasts/*cytology/drug effects/*metabolism MH - HEK293 Cells MH - Humans MH - I-kappa B Kinase/*metabolism MH - I-kappa B Proteins/metabolism MH - Matrix Metalloproteinase 3/metabolism MH - Mice MH - NF-KappaB Inhibitor alpha MH - Phosphorylation/drug effects MH - Phosphoserine/metabolism MH - Promoter Regions, Genetic/*genetics MH - Receptors, Tumor Necrosis Factor/*metabolism MH - Transcription Factor RelB/*metabolism MH - Tumor Necrosis Factor-alpha/pharmacology PMC - PMC4205659 OTO - NOTNLM OT - NF-kappaB OT - TNFalpha OT - metalloproteinase OT - posttranslational modification COIS- The authors declare no conflict of interest. EDAT- 2014/10/01 06:00 MHDA- 2015/05/01 06:00 PMCR- 2015/04/14 CRDT- 2014/10/01 06:00 PHST- 2014/10/01 06:00 [entrez] PHST- 2014/10/01 06:00 [pubmed] PHST- 2015/05/01 06:00 [medline] PHST- 2015/04/14 00:00 [pmc-release] AID - 1410124111 [pii] AID - 201410124 [pii] AID - 10.1073/pnas.1410124111 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14794-9. doi: 10.1073/pnas.1410124111. Epub 2014 Sep 29.