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- Vanlandewijck, Michael, 1982-
(författare)
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Diversification of TGF-β Signaling in Homeostasis and Disease
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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 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.
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| 2. |
- Vanlandewijck, Michael, 1982-, et al.
(författare)
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SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
- 2011
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Transforming growth factor β (TGFβ) is a multifunctional cytokine involved in homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves disassembly of the epithelial adherens and tight junctions and downregulation of several junctional constituents.The mechanism by which TGFβ controls tight junction disassembly is poorly understood. We found that one of the newly identified gene targets of TGFβ, encodes for the serine/threonine kinase SIK (salt-inducible kinase), and controls tight junction assembly by this cytokine. We then identified a new phosphorylation substrate for SIK, the polarity complex protein Par3, which is an important regulator of tight junction assembly. SIK associates with Par3, phosphorylates serine 885 within the atypical protein kinase C-binding domain of Par3, and causes degradation of Par3. Mutation of serine 885 to alanine renders Par3 resistant to degradation induced by SIK. This mechanism is functionally important because both SIK and Par3 participate in the downregulation of tight junctions during EMT initiated by TGFβ signaling. Furthermore, we verified high level SIK expression in several different advanced and invasive human cancers. Notably, high SIK expression correlated with high level TGFβ/Smad signaling activity and with low or undetectable expression of Par3 in human breast cancers. Our model suggests that as the TGFβ signal progresses, SIK gets engaged in a concerted action that lowers signaling by its own receptor and initiates disassembly of the tight junction by acting directly on the polarity complex protein Par3.
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