RESUMO
Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are mediators of many members of the TNF receptor superfamily and can activate both the nuclear factor kappaB (NF-kappaB) and stress-activated protein kinase (SAPK; also known as c-Jun N-terminal kinase) signal transduction pathways. We previously described the involvement of a TRAF-interacting molecule, TRAF-associated NF-kappaB activator (TANK), in TRAF2-mediated NF-kappaB activation. Here we show that TANK synergized with TRAF2, TRAF5, and TRAF6 but not with TRAF3 in SAPK activation. TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR). However, when coexpressed, they formed a strong complex with GCKR, thereby providing a potential mechanism for TRAF and TANK synergy in GCKR-mediated SAPK activation, which is important in TNF family receptor signaling. Our results also suggest that TANK can form potential intermolecular as well as intramolecular interactions between its amino terminus and carboxyl terminus. This study suggests that TANK is a regulatory molecule controlling the threshold of NF-kappaB and SAPK activities in response to activation of TNF receptors. In addition, CD40 activated endogenous GCKR in primary B cells, implicating GCK family proteins in CD40-mediated B-cell functions.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Linfócitos/metabolismo , MAP Quinase Quinase 4 , MAP Quinase Quinase Quinase 1 , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Linfócitos B/metabolismo , Antígenos CD40/metabolismo , Ativação Enzimática , Centro Germinativo/citologia , Quinases do Centro Germinativo , Humanos , MAP Quinase Quinase Quinases/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Tonsila Palatina/citologia , Fragmentos de Peptídeos/metabolismo , Proteínas/genética , Linfócitos T/metabolismo , Fator 2 Associado a Receptor de TNF , Fator 5 Associado a Receptor de TNF , Fator 6 Associado a Receptor de TNFRESUMO
The manner by which natural killer cells discriminate between target and nontarget cells is a subject of intense investigation. Recently, the antigen recognized by the 4F2 monoclonal antibody has been implicated as the target recognition molecule of cloned human natural killer cells. Here we report the results of our studies on the possible role of 4F2 antigen in target recognition by natural killer cells present in the peripheral blood. In our hands, the 4F2 antibody only weakly blocked the killing of K562 leukemia cells by human natural killer cells. Furthermore, no correlation was observed between the level of cell surface 4F2 antigen and the natural killer susceptibility of several tumor cell lines, the ability of these cells to bind to natural killer cells, or the ability of these cell lines to compete with K562 cells in a natural killer assay. Therefore, the 4F2 antigen does not appear to be the target recognition molecule of most peripheral blood natural killer cells.