Transforming Growth Factor-β Cell-Type Specific Signal Transduction

Rod Rahimi

After graduating from Kalamazoo College in Kalamazoo, MI, Rod Rahimi entered the MD-PhD program at Mayo Medical and Graduate Schools. After completing the first two years of medical school, Rod joined the Biochemistry and Molecular Biology Department and is conducting his thesis research in Dr. Edward Leof’s laboratory. The Leof Lab focuses on understanding the function of a cytokine termed Transforming growth factor-β (TGF-β). TGF-β can induce a wide variety of cellular responses depending on the cell type and is implicated in regulating a number of human diseases. For instance, TGF-β induces growth arrest and apoptosis in epithelial cells, responses which have been shown to suppress cancer progression, but induces proliferation, myofibroblast differentiation, and extracellular matrix production in fibroblasts, responses which are implicated in promoting fibrotic diseases. Interestingly, TGF-β induces these various responses by utilizing the same receptor complex. Therefore, therapeutics targeting TGF-β itself or the TGF-β receptor complex in a particular disease state will have unwanted side effects. The Leof Lab is interested in elucidating the cell-type specific intracellular biochemical signals regulated by TGF-β in order to identify therapeutic targets which will give us the potential to modulate some of TGF-β’s functions but not others. Rod’s thesis work involves the identification and characterization of pro-growth signal transduction pathways activated by TGF-β in fibroblasts. Rod has shown that TGF-β causes activation of mammalian Target of Rapamycin (mTOR), a known positive regulator of cell growth, in fibroblasts but not epithelial cells. In the absence of a stimulating signal, a protein termed Tuberin suppresses mTOR’s activity. However, when fibroblasts are stimulated by TGF-β, the receptor complex activates a lipid kinase termed phosphatidylinositol-3 kinase (PI3K) which subsequently activates a serine/threonine kinase Akt. During TGF-β signaling, Akt phosphorylates and inactivates Tuberin, resulting in mTOR activation. Importantly, treatment of fibroblasts with rapamycin, a clinically approved inhibitor of mTOR, prevents TGF-β mediated fibroblast proliferation. These studies suggest that rapamycin alone or in conjunction with other anti-fibrosis therapeutics may be useful in the treatment of fibrotic diseases.