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

Richard H. Weisbart; Grace Chan; Erica Li; Niloofar Farmani; Emil Heinze; Antonia Rubell; Robert N. Nishimura; Keith Colburn

doi:10.1016/j.molimm.2013.02.001

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

Richard H. Weisbart
, Grace Chan
, Erica Li
, Niloofar Farmani
, Emil Heinze
, Antonia Rubell
, Robert N. Nishimura
, Keith Colburn

Loma Linda University

Research output: Contribution to journal › Article › peer-review

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. © 2013 .

Original language	English
Pages (from-to)	247-252
Number of pages	6
Journal	Molecular Immunology
Volume	55
Issue number	3-4
DOIs	https://doi.org/10.1016/j.molimm.2013.02.001
State	Published - Oct 2013

ASJC Scopus Subject Areas

Immunology
Molecular Biology

Keywords

MAPK cascade
Oncogene
Rheumatoid arthritis
NIH 3T3 Cells
Humans
Middle Aged
Recombinant Proteins/genetics
Arthritis, Rheumatoid/genetics
Male
Protein Isoforms/genetics
Proto-Oncogene Proteins B-raf/chemistry
Alternative Splicing/immunology
MAP Kinase Signaling System/immunology
Animals
Adult
Female
Aged
Fibroblasts/immunology
Mice
Matrix Metalloproteinase 14/metabolism
Proto-Oncogene Proteins c-raf/genetics
Synovial Membrane/immunology

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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. {\textcopyright} 2013 .",

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author = "Weisbart, \{Richard H.\} and Grace Chan and Erica Li and Niloofar Farmani and Emil Heinze and Antonia Rubell and Nishimura, \{Robert N.\} and Keith Colburn",

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year = "2013",

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doi = "10.1016/j.molimm.2013.02.001",

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AU - Weisbart, Richard H.

AU - Chan, Grace

AU - Li, Erica

AU - Farmani, Niloofar

AU - Heinze, Emil

AU - Rubell, Antonia

AU - Nishimura, Robert N.

AU - Colburn, Keith

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N2 - 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. © 2013 .

AB - 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. © 2013 .

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KW - Female

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KW - Fibroblasts/immunology

KW - Mice

KW - Matrix Metalloproteinase 14/metabolism

KW - Proto-Oncogene Proteins c-raf/genetics

KW - Synovial Membrane/immunology

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

Abstract

ASJC Scopus Subject Areas

Keywords

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