CYFIP2 is highly abundant in CD4+ cells from multiple sclerosis patients and is involved in T cell adhesion.
DNA microarray profiling of CD4(+) and CD8(+) cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls. Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4(+) cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls. Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients. Several findings indicated that increased levels of CYFIP2 facilitated adhesion. First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion. Secondly, CYFIP2 knock-down experiments using antisense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4(+) cells. Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4(+) cells. Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4(+) cells from MS patients to levels similar to controls. These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.
Mayne
Michael
M
Department of Pharmacology and Therapeutics, University of Manitoba, Division of Neuroscience, St. Boniface Hospital Research Centre, Winnipeg, Canada. michael.mayne@nrc.gc.ca
Moffatt
Teri
T
Kong
Hong
H
McLaren
Paul J
PJ
Fowke
Keith R
KR
Becker
Kevin G
KG
Namaka
Mike
M
Schenck
Annette
A
Bardoni
Barbara
B
Bernstein
Charles N
CN
Melanson
Maria
M
D000328:Adult; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002352:Carrier Proteins