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

MAPK激活的蛋白激酶2(MK2)作为p38的底物，参与多种细胞活动，如转录后调节细胞因子表达、染色质重塑和细胞周期检查点控制等，因此是治疗慢性炎症或癌症的潜在靶分子。MK3是p38的另一个靶点，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这两种激酶进行了广泛的比较分析，但没有发现显着差异。我们现在的目标是通过最近产生的MK3缺陷小鼠的表型特征来研究MK3的功能，特别是在炎症反应和应激诱导的细胞周期停滞方面。为了了解MK3的生物学意义以及MK2和MK3之间的冗余和补偿，我们计划进一步建立MK2/3双KO小鼠品系，并对其细胞因子表达、细胞周期调节和染色质重塑进行鉴定。此外，我们将继续通过亲和纯化和磷蛋白质组学等不同的实验方法来鉴定MK2和MK3的底物，并将应用RAS招募Y2H系统来比较MK2和MK3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.