Biotechnology Ph.D. Programme, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain.
Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBER in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain; Bioelectronics Unit and Nanobioengineering Lab., Institute for Nanoscience and Nanotechnology of the University of Barcelona (IN2UB), Barcelona, Spain.
Comput Biol Med. 2021 Jun;133:104339. doi: 10.1016/j.compbiomed.2021.104339. Epub 2021 Apr 20.
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway involves a three-step cascade of kinases that transduce signals and promote processes such as cell growth, development, and apoptosis. An aberrant response of this pathway is related to the proliferation of cell diseases and tumors. By using simulation modeling, we document that the protein arginine methyltransferase 5 (PRMT5) modulates the MAPK pathway and thus avoids an aberrant behavior. PRMT5 methylates the Raf kinase, reducing its catalytic activity and thereby, reducing the activation of ERK in time and amplitude. Two minimal computational models of the epidermal growth factor (EGF)-Ras-ERK MAPK pathway influenced by PRMT5 were proposed: a first model in which PRMT5 is activated by EGF and a second one in which PRMT5 is stimulated by the cascade response. The reported results show that PRMT5 reduces the time duration and the expression of the activated ERK in both cases, but only in the first model PRMT5 limits the EGF range that generates an ERK activation. Based on our data, we propose the protein PRMT5 as a regulatory factor to develop strategies to fight against an excessive activity of the MAPK pathway, which could be of use in chronic diseases and cancer.
细胞外信号调节激酶 (ERK) 丝裂原活化蛋白激酶 (MAPK) 途径涉及一个三步激酶级联反应，该反应传递信号并促进细胞生长、发育和凋亡等过程。该途径的异常反应与细胞疾病和肿瘤的增殖有关。通过模拟建模，我们记录到蛋白质精氨酸甲基转移酶 5 (PRMT5) 调节 MAPK 途径，从而避免异常行为。PRMT5 甲基化 Raf 激酶，降低其催化活性，从而减少 ERK 的激活时间和幅度。提出了两个受 PRMT5 影响的表皮生长因子 (EGF)-Ras-ERK MAPK 途径的最小计算模型：第一个模型中 PRMT5 被 EGF 激活，第二个模型中 PRMT5 被级联反应刺激。报告的结果表明，PRMT5 在两种情况下都降低了激活 ERK 的时间持续时间和表达，但仅在第一个模型中 PRMT5 限制了产生 ERK 激活的 EGF 范围。基于我们的数据，我们提出蛋白质 PRMT5 作为一种调节因子来制定对抗 MAPK 途径过度活性的策略，这可能对慢性疾病和癌症有用。
