Implication of TNF receptor-I-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation in growth of AIDS-associated Kaposi's sarcoma cells: A possible role of a novel death domain protein MADD in TNF-alpha-induced ERK1/2 activation in Kaposi's sarcoma cells

TNF-alpha is a key pathogenic mediator of infectious and inflammatory disea ses. HIV infection stimulates and dysregulates the immune system, leading t o abnormal production of TNF-alpha. Despite its cytotoxic effect on some tu mor cell lines, TNF-alpha functions as a growth stimulator for Kaposi's sar coma (KS), a common malignancy in HIV-infected patients. However, signaling pathways linked to TNF-alpha-induced mitogenic responses are not well unde rstood. We found that extracellular signal-regulated kinases 1 and 2 (ERK1/ 2) in KS cells were significantly activated by TNF-alpha through tyrosine/t hreonine phosphorylation, Using neutralizing anti-TNFR-I and TNFR-II mAbs, we have now obtained evidence that TNF-alpha-induced KS cell growth and ERK 1/2 activation are mediated exclusively by TNFR-I, not by TNFR-II, A select ive inhibitor fur ERK1/2 activator kinases, PD98059, profoundly inhibited n ot only the activation of ERK1/2, but also the TNF-alpha-induced KS cell pr oliferation. We therefore propose that the TNFR-I-ERK1/2 pathway plays a pi votal role in transmitting to KS cells the mitogenic signals of TNF-alpha. TNFR-I possesses no intrinsic kinase activity, suggesting that TNFR-I-assoc iated proteins may provide a link between TNFR-I and ERK1/2 activation, We found that actinomycin D treatment of KS cells selectively abolished expres sion of mitogen-activated protein kinase-activating death domain protein (M ADD), a novel TNFR-I-associated death domain protein. TNF-alpha failed to i nduce ERK1/2 activation in the actinomycin D-treated cells, MADD may couple TNFR-I with the ERK1/2 signaling pathway required for KS cell proliferatio n.