Diversification of TGF-? Signaling in Homeostasis and Disease

Abstract: With the dawn of metazoans, the ability of cells to communicate with each other became of paramount importance in maintaining tissue homeostasis. The transforming growth factor ? (TGF-?) signaling pathway, which plays important roles during embryogenesis and in the adult organism, signals via a heterodimeric receptor complex consisting of two type II and two type I receptors. After receptor activation through ligand binding, Smads mediate the signal from the receptor complex to the nucleus, where they orchestrate transcription. Depending on the context of activation, TGF-? can mediate a plethora of cellular responses, including proliferation, growth arrest, apoptosis and differentiation. In cancer, TGF-? can act as both as a tumor suppressor and promoter. During early stages of tumorigenesis, TGF-? prevents proliferation. However, TGF-? is also known to promote tumor progression during later stages of the disease, where it can induce differentiation of cancer cells towards a migratory phenotype.The aim of this thesis was to investigate how cells can differentiate their response upon TGF-? pathway activation. The first paper describes the role of Notch signaling in TGF-? induced growth arrest, demonstrating that TGF-? promotes Notch activity and that Notch signaling is required for prolonged TGF-? induced cell cycle arrest. In the second and third paper, we investigate the role of SIK, a member of the AMPK family of kinases, mediating signaling strength of TGF-? through degradation of the TGF-? type I receptor ALK5. While the second paper focuses on the effect of SIK on ALK5 stability and subsequent alterations in TGF-? signaling, the third paper emphasizes cooperation between SIK, Smad7 and the E3 ligase Smurf in degradation of ALK5. Finally, the fourth paper explores a novel role of SIK during TGF-? induced epithelial to mesenchymal transition (EMT). SIK binds to and degrades the polarity protein Par3, leading to enhanced EMT.