Signal transduction by MAPK cascade scaffold proteins

在哺乳动物细胞中，不同的丝裂原活化蛋白激酶（MAPK）级联信号模块的特异性和效率是如何被调节的，以及MAPK和其他类型的信号级联之间的串扰是如何完成的，这些信号级联可能在生长、存活、分化或细胞死亡中发挥作用，目前尚不清楚。解决这些问题的关键分子可能是连接信号模块的支架蛋白。先前我们分离并鉴定了JSAP1和JNKBP1，它们可能作为JNK（MAPK）级联的支架蛋白，通过组织级联成员形成复合物并促进JNK激活。在这项研究中，我们研究了这些支架蛋白如何通过MAPK激酶调节NF-kB信号传导。293T细胞中MEKK1 （MAPKKK）的过表达激活NF-kB，而NF-kB被JSAP1或其他JSAP家族成员JSAP2的共表达所抑制。类似地，JNKBP1的共表达通过MEKK1或TAK1 （MAPKKK）调节NF-kB信号传导。此外，我们确定了293T细胞中支架蛋白和MAPKKKs之间的结合。这些结果表明，支架蛋白JSAP1/2和JNKBP1可能通过与MAPKKKs相互作用来调节JNK和NF-kB信号。

In mammalian cells, it remains uncertain how the specificity and efficiency of distinct mitogen activated protein kinase (MAPK) cascade signaling modules are regulated, and how a cross-talk between the MAPK and other types of signaling cascade that may play a role on growth, survival, differentiation, or cell death, is done. Key molecules to answer these problems may be scaffold proteins that tether their signaling modules. Previously we isolated and characterized JSAP1 and JNKBP1, which may fuction as scaffold proteins of JNK(MAPK) cascades by organizing the formation of the cascade members into complexes and facilitating JNK activation. In this study, we investigated how these scaffold proteins regulate NF-kB signaling by MAPK kinase kinases. Overexpression of MEKK1 (MAPKKK) into 293T cells activated NF-kB, which was repressed by coexpression of JSAP1 or the other JSAP family member JSAP2. Similarly coexpression of JNKBP1 regulated NF-kB signaling by MEKK1 or TAK1 (MAPKKK). Furthermore, we ascertained the binding between the scaffold proteins and MAPKKKs in 293T cells. These results suggest that the scaffold proteins JSAP1/2 and JNKBP1 may regulate both JNK and NF-kB signaling by interacting with MAPKKKs.