title: BRAF splice variants in rheumatoid arthritis synovial fibroblasts activate MAPK through CRAF.
abstract: Rheumatoid arthritis (RA) is a destructive polyarthritis in which synovial-like fibroblasts (SFs) invade and erode cartilage by expressing membrane-anchored type 1 matrix metalloproteinase (MT1-MMP). The mitogen activated protein kinase (MAPK) pathway is activated in RA SFs, but the mechanism of activation is unknown. Here we identify aberrant BRAF splice variants with deletions in both the kinase domain and RAS-binding domain (RBD) in SFs from the majority of RA patients and show that these BRAF splice variants constitutively activate MAPK through CRAF, increase expression of MT1-MMP, and enhance fibroblast invasion of collagen.
authors.affiliation: Veterans Affairs Greater Los Angeles Health Care System, Sepulveda, CA 91343, USA. rweisbar@ucla.edu
authors.forename: Richard H
authors.initials: RH
authors.lastname: Weisbart
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.forename: Erica
authors.initials: E
authors.lastname: Li
authors.forename: Niloofar
authors.initials: N
authors.lastname: Farmani
authors.forename: Emil
authors.initials: E
authors.lastname: Heinze
authors.forename: Antonia
authors.initials: A
authors.lastname: Rubell
authors.forename: Robert N
authors.initials: RN
authors.lastname: Nishimura
authors.forename: Keith
authors.initials: K
authors.lastname: Colburn
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D041681:NIH 3T3 Cells; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D011994:Recombinant Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14