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Diversification of TGF-β Signaling in Homeostasis and Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research. (TGF-ß signaling group)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 679
Keyword [en]
TGF-β, signaling, SIK, EMT, polarity, Notch, ALK5, p21, growth arrest, Smurf, Smad7, receptor, SNF1LK
National Category
Cell and Molecular Biology
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-152267ISBN: 978-91-554-8098-1OAI: oai:DiVA.org:uu-152267DiVA: diva2:413179
Public defence
2011-06-11, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2011-05-20 Created: 2011-04-27 Last updated: 2011-07-01Bibliographically approved
List of papers
1. Notch signaling is necessary for epithelial growth arrest by TGF-beta
Open this publication in new window or tab >>Notch signaling is necessary for epithelial growth arrest by TGF-beta
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2007 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 176, no 5, 695-707 p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF-beta) and Notch act as tumor suppressors by inhibiting epithelial cell proliferation. TGF-beta additionally promotes tumor invasiveness and metastasis, whereas Notch supports oncogenic growth. We demonstrate that TGF-beta and ectopic Notch1 receptor cooperatively arrest epithelial growth, whereas endogenous Notch signaling was found to be required for TGF-beta to elicit cytostasis. Transcriptomic analysis after blocking endogenous Notch signaling uncovered several genes, including Notch pathway components and cell cycle and apoptosis factors, whose regulation by TGF-beta requires an active Notch pathway. A prominent gene coregulated by the two pathways is the cell cycle inhibitor p21. Both transcriptional induction of the Notch ligand Jagged1 by TGF-beta and endogenous levels of the Notch effector CSL contribute to p21 induction and epithelial cytostasis. Cooperative inhibition of cell proliferation by TGF-beta and Notch is lost in human mammary cells in which the p21 gene has been knocked out. We establish an intimate involvement of Notch signaling in the epithelial cytostatic response to TGF-beta.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10286 (URN)10.1083/jcb.200612129 (DOI)000244487100026 ()17325209 (PubMedID)
Available from: 2007-03-12 Created: 2007-03-12 Last updated: 2012-03-14Bibliographically approved
2. TGFβ induces SIK to negatively regulate type I receptor kinase signaling
Open this publication in new window or tab >>TGFβ induces SIK to negatively regulate type I receptor kinase signaling
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2008 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 182, no 4, 655-662 p.Article in journal (Refereed) Published
Abstract [en]

Signal transduction by transforming growth factor beta (TGFbeta) coordinates physiological responses in diverse cell types. TGFbeta signals via type I and type II receptor serine/threonine kinases and intracellular Smad proteins that regulate transcription. Strength and duration of TGFbeta signaling is largely dependent on a negative-feedback program initiated during signal progression. We have identified an inducible gene target of TGFbeta/Smad signaling, the salt-inducible kinase (SIK), which negatively regulates signaling together with Smad7. SIK and Smad7 form a complex and cooperate to down-regulate the activated type I receptor ALK5. We further show that both the kinase and ubiquitin-associated domain of SIK are required for proper ALK5 degradation, with ubiquitin functioning to enhance SIK-mediated receptor degradation. Loss of endogenous SIK results in enhanced gene responses of the fibrotic and cytostatic programs of TGFbeta. We thus identify in SIK a negative regulator that controls TGFbeta receptor turnover and physiological signaling.

Place, publisher, year, edition, pages
The Rockefeller University Press, 2008
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-103239 (URN)10.1083/jcb.200804107 (DOI)000259050000007 ()18725536 (PubMedID)
Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2012-03-14Bibliographically approved
3. SIK and Smurf2 cooperate to downregulate the TGF-β type I receptor
Open this publication in new window or tab >>SIK and Smurf2 cooperate to downregulate the TGF-β type I receptor
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-128850 (URN)
Available from: 2010-07-27 Created: 2010-07-27 Last updated: 2012-03-14
4. SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
Open this publication in new window or tab >>SIK phosphorylates and degrades Par3 to mediate tight junction disassembly during epithelial-mesenchymal transition
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2011 (English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

230 p.
Keyword
EMT, Par3, Signal transduction, SIK, TGFβ
Identifiers
urn:nbn:se:uu:diva-152266 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2012-03-14

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