Abstract
Non-reversible fibrosis is common in various diseases such as chronic renal failure, liver cirrhosis, chronic pancreatitis, pulmonary fibrosis, rheumatoid arthritis and atherosclerosis. Transforming growth factor beta 1 (TGF-β1) is involved in virtually all types of fibrosis. We previously described the involvement of Ras GTPase isoforms in the regulation of TGF-β1-induced fibrosis. The guanine nucleotide exchange factor Son of Sevenless (Sos) is the main Ras activator, but the role of the ubiquitously expressed Sos1 in the development of fibrosis has not been studied. For this purpose, we isolated and cultured Sos1 knock-out (KO) mouse embryonic fibroblasts, the main extracellular matrix proteins (ECM)-producing cells, and we analyzed ECM synthesis, cell proliferation and migration in the absence of Sos1, as well as the role of the main Sos1-Ras effectors, Erk1/2 and Akt, in these processes. The absence of Sos1 increases collagen I expression (through the PI3K-Akt signaling pathway), total collagen proteins, and slightly increases fibronectin expression; Sos1 regulates fibroblast proliferation through both PI3K-Akt and Raf-Erk pathways, and Sos1-PI3K-Akt signaling regulates fibroblast migration. These study shows that Sos1 regulates ECM synthesis and migration (through Ras-PI3K-Akt) and proliferation (through Ras-PI3K-Akt and Ras-Raf-Erk) in fibroblasts, and describe for the first time the role of the Sos1-Ras signaling axis in the regulation of cellular processes involved in the development of fibrosis.
Highlights
In most cases, when organs suffer injuries motivated by different disorders or diseases, a complex cascade of cellular and molecular responses triggering fibrosis of the tissue begins
We analyzed the changes induced by the absence of Sos1 in the activation of two of the main intracellular pathways stimulated by Ras: rapidly accelerated fibrosarcoma (Raf)mitogen-activated protein kinase (MAPK) cascade, whose final effect is the phosphorylation of extracellular signal-regulated kinases (Erk), and the phosphatidylinositol 3kinases pathway (PI3K) that leads to phosphorylation of Akt
We stimulated fibroblasts with transforming growth factor beta-1 (TGF-β1), the main cytokine involved in fibrotic processes and in the synthesis of extracellular matrix proteins (ECM)
Summary
In most cases, when organs suffer injuries motivated by different disorders or diseases, a complex cascade of cellular and molecular responses triggering fibrosis of the tissue begins. When this phenomenon occurs over a prolonged period of time, this ends up causing irreversible parenchymal damage, cellular dysfunction and functional failure of the organ (Rockey et al, 2015). This process is common in many diseases such as chronic renal failure, liver cirrhosis, chronic pancreatitis, pulmonary fibrosis, rheumatoid arthritis, and atherosclerosis.
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