Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein kinase c-Jun N-terminal kinase) activation - IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation

We have shown recently that interleukin (IL)-2 activates the mitogen-activa ted protein (MAP) kinase family members p38 (HOG1/stress-activated protein kinase II) and p54 (c-Jun N-terminal kinase/stress-activated protein kinase I). Furthermore, the p38 MAP kinase inhibitor SB203580 inhibited IL-2-driv en T cell proliferation, suggesting that p38 MAP kinase might be involved i n mediating proliferative signals. In this study, using transfected BA/F3 c ell lines, it is shown that both the acidic domain and the membrane-proxima l serine-rich region of the IL-2R beta chain are required for p38 and p54 M AP kinase activation and that, as for p42/44 MAP kinase, this activation re quires the Tyr(338) residue of the acidic domain, the binding site for She. It is well established that the acidic domain of the IL-2R beta chain is d ispensable for IL-a-driven proliferation, and thus our observations suggest that neither p38 nor p54 MAP kinase activation is required for IL-a-driven proliferation of BA/F3 cells. In addition, the tetravalent guanylhydrazone inhibitor of proinflammatory cytokine production, CNI-1493, can block the activation of p54 and p38 MAP kinases by IL-2 but has no effect on IL-2-dri ven proliferation of BA/F3 cells, activated primary T cells, or a cytotoxic T cell line. Furthermore, our observations provide evidence for the existe nce of an additional, unknown target of the p38 MAP kinase inhibitor SB2035 80, the activation of which is essential for mitogenic signaling by IL-2.