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Role of β1 integrin and its signaling molecule, Cas-L, in pathophysiology and therapeutic interventigens of rheumatoid arthritis

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Accumulating evidences suggest that β1 integrin-dependent cell activation and migration pathways are critical points of intervention in several inflammatory and autoimmune diseases, such as rheumatoid arthritis (RA). Indeed, in RA patients, increased expression of β1-integrins and their ligands have been reported on the surface of synovial fluid lymphocytes and synovium cells, respectively, suggesting that β1 integrins play an important role in triggering and maintaining the inflammatory response of the disease.

It is reported that tyrosine phosphorylation of cellular proteins is an early obligatory event in cell activation and signal transduction. Our study showed that PLC-γ, focal adhesion kinase (FAK), paxillin, Fyn, Lck, ERK1/2, and pp105 are phosphorylated on their tyrosine residues upon engagement of β1 integrins in T cells. Moreover, we have demonstrated that the pp105 has been shown to associate with FAK that is autophosphorylated and activated upon the engagement of β1 integrins. In addition, isolation of cDNA encoding pp105 has revealed that this protein belongs to the Crk-associated substrate (Cas) family, hence designated the Cas-lymphocyte type (Cas-L). Cas-L is a 105 kDa docking protein that is heavily tyrosine phosphorylated by FAK and Src family kinases upon the engagement of β1 integrins in T cells. Transfection of Cas-L into Jurkat T cells markedly enhances cell motility and IL-2 production upon the engagement of β1 integrins through its tyrosine phosphorylation. These results clearly indicate the involvement of Cas-L in β1 integrin-mediated costimulation of signal transduction and cell migration. Our current study on Yeast-Two-hybrid analysis identified HTLV-I Tax and Smad-7 as new candidates for the Cas-L binding partner. I would now like to review β1 integrin-mediated signal transduction through Cas-L, a novel docking protein, and its role in the pathophysiology and therapeutic intervention of RA.

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  • Rheumatoid Arthritis
  • Integrin
  • Rheumatoid Arthritis Patient
  • Focal Adhesion Kinase
  • Tyrosine Phosphorylation