BRAF splice variants in rheumatoid arthritis synovial fibroblasts activate MAPK through CRAF

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.

► RA synovial fibroblasts contain aberrant BRAF splice variants.
► Aberrant BRAF splice variants constitutively activate MAPK through CRAF.
► The binding site on BRAF for CRAF is identified as a possible therapeutic target for RA.