The role of EMC3 protein in the Ras-induced tumorigenesis in Drosophila melanogaster and in human cell line

Abstract

The endoplasmic reticulum is an essential organelle for the functioning of the eukaryotic cell. It is responsible for various processes, such as protein synthesis, folding and post-translational modification. Although most of these cellular processes are well known, there are many proteins identified or predicted in important cell pathways that remain uncharacterized. The transmembrane protein complex EMC (Endoplasmatic Reticulum Membrane Complex) is one of them. The EMC proteins are highly conserved in eukaryotes, encompassing ten subunits in mammals (mEMCs), nine in Drosophila melanogaster, and six in yeast. They interact to form a complex whose functions are still poorly understood. More recent studies have highlighted the importance of the EMC complex for post-translational modifications (PTMs), especially for transmembrane proteins. Intracellular signaling pathways are predominantly activated by transmembrane receptors and plasma membrane (PM) associated proteins. These proteins must undergo appropriate post-translational changes for their correct insertion or anchorage in the endoplasmic reticulum membrane and PM. The Ras proteins are coupled to the inner face of MP, being the most commonly recruited proteins to trigger proliferative signals in different types of cancer. Indeed, the Ras proto-oncogenes (H-Ras, N-Ras and K-Ras) are the most frequently mutated genes in human cancers that are the most difficult to treat. Interestingly, the Ras PTMs, such as folding, proteolysis, methylation and lipidation occur in the endoplasmic reticulum, the organelle where the EMC complex is resident. In addition, protein-protein interactions have been reported between EMC3 and proteins such as EGFR, which is responsible for activating the RAS-RAF-MEK-ERK pathway, even as RAB5A (Ras-related Protein), a GTPase protein associated with EGFR trafficking to the PM. Curiously, the mechanisms underlying such interactions remain unclear. Therefore, the potential functional interactions of EMCs, especially the EMC3 subunit, with Ras PTMs pathways support the hypothesis of a new role for the EMC complex in the insertion of Ras into PM and activation of the RAS-RAF-MEK-ERK pathway of cell proliferation.