Stochastic modulation evidences a transitory EGF-Ras-ERK MAPK activity induced by PRMT5. (June 2021)

• Record Type: Journal Article
• Authors: Jurado, Manuel; Castaño, Óscar; Zorzano, Antonio
• Is Part Of: Computers in biology and medicine. Volume 133(2021)
• Publication Date: 2021-06
• Subjects: Cell response modulation -- Cancer -- MAPK pathway -- EGF-Ras-ERK signaling Route -- PRMT5 -- Methylation -- Computational model; Medicine -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; 610.285
• DOI: 10.1016/j.compbiomed.2021.104339
• Languages: English
• ISSNs: 0010-4825

Abstract

Abstract: 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. Highlights: Presentation of a computational model of EGF-Ras-ERK pathway with PRMT5 activity. PRMT5 activity is regulated by either input stimuli or pathway output response. The regulatory protein PRMT5 limits the ERK activity, amplitude and duration. PRMT5 reduces the range of EGF stimulus able of generating ERK response. PRMT5 upregulation is a strategy to cope against indications characterized by excessive MAPK activity.