Stromal cell-derived factor-1-induced LFA-1 activation during in vivo migration of T cell hybridoma cells requires G(q/11), RhoA, and myosin, as wellas G(i) and Cdc42

Dissemination of T cell hybridomas in mice, a model for in vivo migration o f memory T cells and for T lymphoma metastasis, depends on the chemokine st romal cell-derived factor-1 (SDF-1) and the integrin LFA-1 and correlates w ell with invasion into fibroblast cultures. In addition to the known role o f the pertussis toxin-sensitive heterotrimeric GTPase G(i), we show that al so the pertussis toxin-insensitive GTPase G(q/11) is required for dissemina tion and invasion. Furthermore, we show that the small GTPases, Cdc42 and R hoA, are involved, and that invasion is blocked by inhibitors of actinomyos in contraction. G(q/11), RhoA, and contraction are specifically required fo r LFA-1 activation, since 1) they are essential for LFA-1-dependent migrati on toward low SDF-1 concentrations through ICAM-1-coated filters, but not f or migration toward high SDF-1 levels, which is LFA-I independent; 2) G pro tein (AIF(4)(-))-induced adhesion to ICAM-1 requires RhoA and contraction; 3) constitutively active G(q) induces aggregation, mediated by LFA-1. We pr eviously reported that binding of this activated LFA-1 to ICAM-1 triggers a signal, transduced by the zeta -associated protein 70 tyrosine kinase, tha t activates additional LFA-1 molecules. This amplification of LFA-1 activat ion is essential for invasion. We show here that zeta -associated protein 7 0-induced LFA-1 activation requires neither Cdc42 and RhoA nor contraction and is thus quite different from that induced by SDF-1. We conclude that tw o modes of LFA-I activation, with distinct underlying mechanisms, are requi red for the in vivo migration of T cell hybridomas.