Diversification of TGF-β Signaling in Homeostasis and Disease
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
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 β (TGF-β) 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-β can mediate a plethora of cellular responses, including proliferation, growth arrest, apoptosis and differentiation. In cancer, TGF-β can act as both as a tumor suppressor and promoter. During early stages of tumorigenesis, TGF-β prevents proliferation. However, TGF-β 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-β pathway activation. The first paper describes the role of Notch signaling in TGF-β induced growth arrest, demonstrating that TGF-β promotes Notch activity and that Notch signaling is required for prolonged TGF-β 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-β through degradation of the TGF-β type I receptor ALK5. While the second paper focuses on the effect of SIK on ALK5 stability and subsequent alterations in TGF-β 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-β induced epithelial to mesenchymal transition (EMT). SIK binds to and degrades the polarity protein Par3, leading to enhanced EMT.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 679
TGF-β, signaling, SIK, EMT, polarity, Notch, ALK5, p21, growth arrest, Smurf, Smad7, receptor, SNF1LK
Cell and Molecular Biology
Research subject Biology with specialization in Molecular Cell Biology
IdentifiersURN: urn:nbn:se:uu:diva-152267ISBN: 978-91-554-8098-1OAI: oai:DiVA.org:uu-152267DiVA: diva2:413179
2011-06-11, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Dooley, Steven, Professor
Moustakas, Aristidis, PhDHeldin, Carl-Henrik, Professor
List of papers