Cas-L associates with human T-lymphotropic virus type I Tax and regulates its transactivation of NF-κB: possible role of Cas-L in pathophysiology of rheumatoid arthritis

The Crk-associated substrate lymphocyte type (Cas-L) is a 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 cells markedly enhances cell motility and IL-2 production by 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. We have recently reported that expression of Cas-L is markedly elevated in human T-lymphotropic virus type I (HTLV-I) tax transgenic mouse, a murine model for rheumatoid arthritis, as well as in rheumatoid arthritis patients.

In the present study, we show the interaction of Cas-L and Tax, and its biological significance in detail.

We initially found that tyrosine phosphorylation as well as the expression of Cas-L was markedly elevated through the induction of HTLV-I Tax protein in JPX-9 cells, in which Tax is induced under the control of metallothionein promoter. Biochemical study showed that autophosphorylation of Src family PTKs, fyn and lck, were significantly enhanced in correlation to tyrosine phosphorylation of Cas-L. Consistent with our previous result, it was revealed that those cells had remarkably increased motile behavior on a fibronectin-coated Transwell insert.

A two-hybrid screen for Cas-L binding proteins resulted in identification of Tax as one of the candidates for Cas-L binding partners. We subsequently confirmed protein–protein interaction of Cas-L and Tax using an overexpression experiment and HTLV-I transformed T-cell lines.

Finally, expression of Cas-L was found to inhibit Tax-mediated transactivation of NF-κB, whereas it has virtually no effects on Tax-mediated transactivation of HTLV-I LTR.

To date, HTLV-I has been associated with a variety of diseases affecting organs other than malignancies arising from the lymphoid system. Those chronic inflammatory diseases involve the nervous system in HTLV-I-associated myelopathy, the eyes in HTLV-I-associated uveitis, the salivary glands in Sjögren's syndrome, and the articular joints in the case of HTLV-I-associated arthropathy.

These results may present the basis for a pathological role as well as for therapeutic application of Cas-L in HTLV-I-related inflammatory diseases.