SIGNAL TRANSDUCTION IN B LYMPHOCYTES: INDENTIFICATION OF KEY SIGNALING MOLECULE

这个项目继续关注两个蛋白激酶，GCKR和GCK。这些都是哺乳动物的丝氨酸/苏氨酸蛋白激酶，属于蛋白激酶的一个亚家族，还包括GLK、HPK1和NIK。它们的特征是一个与酵母STE20蛋白激酶相关的N-末端激酶结构域，一个大的C-末端调节域，以及激活应激激活蛋白激酶(SAPK)的能力，也被称为Jun激酶或JNK途径。该通路被多种细胞应激激活，如炎性细胞因子肿瘤坏死因子和CD40配体(CD40L)。CD40L存在于活化的T淋巴细胞上，并与其受体CD40相互作用，CD40在免疫系统中的许多重要细胞上表达，包括树突状细胞、单核细胞和B淋巴细胞。先前我们发现GCK和GCKR是肿瘤坏死因子介导的SAPK激活的主要中介。此外，肿瘤坏死因子信号导致GCKR向肿瘤坏死因子受体相关因子-2(TRAF-2)募集。我们扩展了这些研究，发现CD40信号也可以诱导GCKR激活。GCKR的激活会导致SAPK通路的激活。另一种与肿瘤坏死因子受体相关的分子称为TANK，与TRAF2和GCKR形成三分子复合体。这稳定了TRAF2和GCKR之间的相互作用。最后，我们已经证明了CRK家族的成员与GCKR结合，从而可能将GCKR与其他信号分子联系起来。-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.