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Post-translational regulation of RAS by the EMC complex: a potential target for anti-oncogenic therapy

Grant number: 19/01285-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): May 01, 2019
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Enilza Maria Espreafico
Grantee:Airton de Carvalho Junior
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID

Abstract

The transmembrane protein complex of the endoplasmic reticulum EMC is a group of highly conserved proteins in eukaryotes involved in post-translational modifications of transmembrane proteins and phospholipid biosynthesis. However, the molecular and biochemical mechanisms of the EMCs functions in these processes are still poorly characterized. The intracellular signaling pathways are, predominantly, activated by transmembrane receptors and signal transducing proteins anchored to the plasma membrane, which must undergo appropriate post-translational modifications for their correct insertion or anchoring in the endoplasmic reticulum membrane and the plasma membrane. The RAS protein isoforms are the most widely recruited protein to transmit proliferation signals in different types of Cancers and their respective proto-oncogenes (HRAS, NRAS and KRAS) are among the most frequently mutated genes in human Cancers, leading to very difficult Cancers to treat. Post-translational regulation of RAS occurs primarily in the endoplasmic reticulum and basically includes the steps of farnesylation, proteolytic processing, methylation, and palmitoylation, which are essential processes to enable its anchoring to the plasma membrane. Interestingly, recent studies have demonstrated functional interactions among members of the EMC complex and proteins, such as, methyl, farnesyl and palmitoyltransferases, as well as membrane receptors such as EGFR, responsible for the activation of the RAS-RAF-MEK-ERK cell signaling pathway. Therefore, post-translational modifications of RAS in the endoplasmic reticulum constitute a potential cell pathway in which EMCs could play key roles, especially in the folding and lipidation steps. The therapeutic approaches developed to treat Cancer by targeting the RAS oncoproteins are based essentially on blocking the farnesilation step, but they have not been effective due to alternative mechanisms of lipidation that allow for the RAS protein anchorage to the plasma membrane and activation. Thus, to elucidate the roles of EMCs in the post-translational modifications and regulation of RAS may bring novel insights into the field for the development of more effective anti-oncogenic therapies. (AU)