SIGNAL TRANSDUCTION IN B LYMPHOCYTES: INDENTIFICATION OF KEY SIGNALING MOLECULE

该项目继续关注两种蛋白激酶，GCKR和GCK。这些是属于蛋白激酶亚家族的哺乳动物丝氨酸/苏氨酸蛋白激酶，其还包括GLK、HPK 1和NIK。它们的特征在于与酵母STE 20蛋白激酶相关的N-末端激酶结构域、大的C-末端调节结构域和激活应激活化蛋白激酶（SAPK，也称为Jun激酶或JNK）途径的能力。该途径被许多细胞应激激活，炎性细胞因子肿瘤坏死因子（TNF）和CD 40配体（CD 40 L）。CD 40 L存在于活化的T淋巴细胞上，并与其反受体CD 40相互作用，后者由免疫系统中的许多重要细胞表达，包括树突状细胞、单核细胞和B淋巴细胞。以前，我们表明，GCK和GCKR是TNF介导的SAPK激活的主要中介。此外，TNF信号传导导致GCKR募集至TNF受体相关因子-2（TRAF-2）。我们已经扩展了这些研究，并表明CD 40信号也诱导GCKR激活。GCKR的激活导致SAPK通路的激活。另一种称为TANK的TNF受体相关分子与TRAF 2和GCKR形成三分子复合物。这稳定了TRAF 2和GCKR之间的相互作用。最后，我们已经表明，接头蛋白的Crk家族的成员结合GCKR，从而可能连接GCKR的其他信号分子。- GCK、GCKR、SAPK、TNF、CD40。

This project continues to focus on two protein kinases, GCKR and GCK. These are mammalian serine/threonine protein kinases that belong to a subfamily of protein kinases, which also includes GLK, HPK1, and NIK. They are characterized by an N-terminal kinase domain related to the yeast STE20 protein kinase, a large C-terminal regulatory domain, and the ability to activate the stress-activated protein kinase (SAPK, also referred to as Jun kinase or JNK) pathway. This pathway is activated by many cellular stresses, the inflammatory cytokine tumor necrosis factor (TNF) and CD40 ligand (CD40L). CD40L is present on activated T lymphocytes and interacts with its counter-receptor CD40, which is expressed by many on the important cells in the immune system, including dendritic cells, monocytes, and B-lymphocytes. Previously we showed that GCK and GCKR are major intermediaries in TNF-mediated SAPK activation. In addition, TNF signaling leads to the recruitment of GCKR to TNF receptor associated factor-2 (TRAF-2). We have extended those studies and shown that CD40 signaling also induces GCKR activation. GCKR activation then leads to activation of the SAPK pathway. Another TNF receptor associated molecule called TANK forms a trimolecular complex with TRAF2 and GCKR. This stabilizes the interaction between TRAF2 and GCKR. Finally, we have shown that members of the Crk family of adaptor proteins bind to GCKR and thus may link GCKR to other signaling molecules. - GCK, GCKR, SAPK, TNF, CD40.