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.
Published by Elsevier Ltd.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adult
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Aged
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Alternative Splicing / immunology
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Animals
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Arthritis, Rheumatoid / genetics*
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Arthritis, Rheumatoid / immunology
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Arthritis, Rheumatoid / metabolism*
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Female
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Fibroblasts / immunology
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Fibroblasts / metabolism
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Humans
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MAP Kinase Signaling System* / immunology
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Male
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Matrix Metalloproteinase 14 / metabolism
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Mice
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Middle Aged
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NIH 3T3 Cells
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Proto-Oncogene Proteins B-raf / chemistry
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins B-raf / metabolism*
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Synovial Membrane / immunology
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Synovial Membrane / metabolism
Substances
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Protein Isoforms
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Recombinant Proteins
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-raf
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MMP14 protein, human
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Matrix Metalloproteinase 14