Cell type specific TGF-β induced activation of Erk1/2

Hough, Christopher Michael (2008) Cell type specific TGF-β induced activation of Erk1/2. Masters thesis, Memorial University of Newfoundland.

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Abstract

The Transforming Growth Factor-Beta (TGF-β) family is a collection of structurally related peptides. These growth factors are involved in a variety of cellular processes such as apoptosis, differentiation, and proliferation. TGF-β binding to a Serine/Threonine kinase receptor complex causes the recruitment and subsequent activation of transcription factors known as Smad2 and Smad3. These proteins then translocate into the nucleus and either negatively or positively regulate gene expression. TGF-β acts in a cell type specific manner; cellular proliferation is induced in mesenchymal cells and inhibited in epithelial cells. In this study, we define a novel Smad-independent pathway leading to the phosphorylation of extracellular signal regulated kinase (Erk) in a cell type dependent fashion. Erk activation is seen in mesenchymal cells, but not in cells of epithelial origin. Phosphotidylinositol3-Kinase (PI3K) appears to function upstream of Erk by activating cdc42/Racl and subsequently p21-Activated Kinase2 (PAK2). P AK2 activity was shown to be integral to Erk activation through the phosphorylation of c-Raf at Ser338, a site important for c-Raf activity. The MEK kinases were found to act directly upstream of Erk as the presence of U0126 abolishes TGF-β induced Erk phosphorylation. Furthermore, Erk activity is critical in TGF-β induced fibroblast proliferation, likely through its interactions with transcription factors such as Smads and c-myc. Moreover, we have shown a direct interaction between Erk and Smads during TGF-β stimulation. Phosphorylation of Serine residues 245, 250, and 255 within the linker region of Smad2 was observed after induction of Erk. Interestingly, this phosphorylation event was localized within the nucleus. Together, this data shows a new signaling pathway utilized by TGF-β receptors that interacts with and regulates the classical Smad signaling pathway and TGF-β induced proliferation in fibroblasts.

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