Further analysis of MK2/MK3 double knockout mice: p38 signaling, tumorigenesis and cell migration

MAPK活化的蛋白激酶2（MAPK activated protein kinase 2，MK 2）作为p38的底物，参与多种细胞活动，如细胞因子表达的转录后调节、染色质重塑和细胞周期检查点控制等，是治疗慢性炎症或癌症的潜在靶分子。p38的另一个靶点MK 3与MK2蛋白高度同源。在我们的初步研究中，我们在体外和体内实验中对两种激酶进行了广泛的比较分析，没有发现显着差异。我们的目标是通过最近生产的MK 3缺陷小鼠的表型特征来研究MK 3功能，特别是在炎症反应和应激诱导的细胞周期停滞中。为了了解MK 3的生物学意义以及MK2和MK 3之间的冗余和补偿，我们进一步计划生产MK2/3双KO小鼠品系并在细胞因子表达、细胞周期调控和染色质重塑方面进行表征。此外，我们将继续通过使用不同的实验方法，如亲和纯化和磷蛋白质组学来鉴定MK2和MK 3的底物，并将应用Ras募集Y2 H系统来比较MK2和MK 3的蛋白质相互作用和支架。

MAPK-activated protein kinase 2 (MK2) as a substrate of p38 is involved in diverse cellular activities, such as posttranscriptional regulation of cytokine expression, chromatin remodelling and cell cycle checkpoint control and, hence, is a potential target molecule for therapy of chronic inflammation or cancer. MK3, another target of p38, is highly homologous to MK2 protein. In our preliminary studies we performed extensive comparative analysis of both kinases in in vitro and in vivo experiments without identifying significant differences. Our aim is now to study MK3 function by phenotypic characterisation of recently produced MK3-deficient mice especially in inflammatory response and stress-induced cell cycle-arrest. To understand the biological significance of MK3 as well as the redundancy and compensation between MK2 and MK3, we further plan to produce and characterize MK2/3 double KO mouse strain in cytokine expression, cell cycle regulation and chromatin remodelling. Furthermore, we will continue to identify substrates of MK2 and MK3 by using different experimental approaches such as affinity purification and phosphor-proteomics and will apply a Ras-recruitment Y2H system to compare protein interaction and scaffolding for MK2 and MK3.