Cancer: MAPK phosphorylation and nuclear translocation

描述（由申请人提供）：促分裂原活化蛋白激酶（MAPK）是一个高度保守的蛋白丝氨酸/苏氨酸激酶家族，参与酵母、蝇和哺乳动物的信号转导途径，并响应多种信号而活化。在哺乳动物中，MARK蛋白p42/p44（也称为ERK 1/2）磷酸化并激活细胞质和细胞核中的许多靶标，并且在细胞培养系统中，MAPK的亚细胞定位与随后引发的细胞应答之间存在强相关性。然而，我们实验室的初步数据表明，MAPK在易位到细胞核后，即使没有磷酸化，也可以促进细胞增殖。因此，我计划直接测试这一建议，有以下两个具体目标：1）MAPK磷酸化是否是MAPK核转位和细胞周期进程所必需的？（2）在细胞周期调控中，哪些因素介导MAPK的胞质定位和胞核转位？由于Ras/MAPK通路的改变与大约25%的人类肿瘤相关，因此更深入地了解MAPK核转位如何影响这一过程可以增强我们对人类癌症的理解。

DESCRIPTION (provided by applicant): Mitogen-activated protein kinases (MAPKs) are a highly conserved family of protein serine/ threonine kinases involved in signal transduction pathways in yeast, flies, and mammals, and are activated in response to a variety of signals. In mammals, MARK proteins p42/p44 (also called ERK 1/2) phosphorylate and activate a number of targets in both the cytoplasm and the nucleus, and in cell culture systems, a strong correlation exists between the subcellular localization of MAPK and the subsequent cellular responses elicited. However, preliminary data from our lab suggests that MAPK can function to promote cell proliferation after translocation to the nucleus even when it does not become phosphorylated. I therefore plan to test this suggestion directly, with the following two specific aims: 1) Is MAPK phosphorylation required for MAPK nuclear translocation and cell cycle progression?, and 2) What are the factors mediating MAPK hold in the cyoplasm vs. translocation to the nucleus in cell cycle regulation? As alterations in the Ras/MAPK pathway are associated with approximately 25% of human tumors, a deeper understanding of how MAPK nuclear translocation affects this process could enhance our understanding of human cancers.