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Regulation of TGF-β Signaling by Post-Translational Modifications
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor-β (TGF-β) signaling is initiated when the ligand binds to type II and type I serine/threonine kinase receptors at the cell surface. Activated TGF-β type I receptors phosphorylate R-Smads which relocate, together with co-Smads, to the cell nucleus and regulate transcription. Enhancement or repression of Smad-specific gene targets leads to intracellular protein compositions which organize functional complexes and thus govern cellular processes such as proliferation, migration and differentiation.

TGF-β/Smad signaling relays are regulated by various post-translational modifications. From receptors to gene promoters, intricate interplays between phosphorylation, acetylation, ubiquitination and numerous other modifications, control Smad signaling initiation and duration. However, many steps in the cascade, including receptor internalization, Smad nuclear shuttling and transcriptional termination, still remain elusive. The open gaps in our understanding of these mechanisms most likely involve additional post-translational regulations. Thus, the aim of the present investigation was to identify novel modulators of TGF-β/Smad signaling.

In the first part of this thesis, we show the importance of ADP-ribosylation in Smad-mediated transcription. We identified poly(ADP-ribose) polymerase 1 (PARP-1) as a Smad interacting protein. Our work revealed that PARP-1 forms direct interactions with Smad3/4, and PARylates residues in their MH1 domains. This modification restricts Smads from binding to DNA and attenuates Smad-activated transcription. PARylation is reversed by the glycohydrolase PARG. We provide evidence that PARG can de-ADP-ribosylate Smads, which enhances Smad-promoted gene regulation.

In the second part, we examine a Smad-dependent gene target of TGF-β signaling, salt inducible kinase 1 (SIK). After induction, SIK cooperates with Smad7 and Smurf2 to downregulate the TGF-β type I receptor. The mechanism relies on both the kinase and UBA domain of SIK as well as the E3-ligase activity of Smurf2.

In summary, we have unveiled two enzyme-dependent TGF-β/Smad modulatory mechanisms; SIK promoted receptor turnover and PARP-1/PARG-regulated Smad signaling.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 59
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 577
Keywords [en]
TGF-β, Smad, PARP-1, PARG, ALK5, SIK, signal transduction, transcription, post-translational modification, phosphorylation, ubiquitin, ADP-ribosylation, DNA-binding, receptor degradation
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-128855ISBN: 978-91-554-7844-5 (print)OAI: oai:DiVA.org:uu-128855DiVA, id: diva2:331945
Public defence
2010-09-10, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-08-20 Created: 2010-07-27 Last updated: 2010-08-30Bibliographically approved
List of papers
1. PARP-1 attenuates Smad-mediated transcription
Open this publication in new window or tab >>PARP-1 attenuates Smad-mediated transcription
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2010 (English)In: Molecular Cell, ISSN 1097-2765, E-ISSN 1097-4164, Vol. 40, no 4, p. 521-532Article in journal (Refereed) Published
Abstract [en]

The versatile cytokine transforming growth factor β (TGF-β) regulates cellular growth, differentiation, and migration during embryonic development and adult tissue homeostasis. Activation of TGF-β receptors leads to phosphorylation of Smad2 and Smad3, which oligomerize with Smad4 and accumulate in the nucleus where they recognize gene regulatory regions and orchestrate transcription. Termination of Smad-activated transcription involves Smad dephosphorylation, nuclear export, or ubiquitin-mediated degradation. In an unbiased proteomic screen, we identified poly(ADP-ribose) polymerase-1 (PARP-1) as a Smad-interacting partner. PARP-1 dissociates Smad complexes from DNA by ADP-ribosylating Smad3 and Smad4, which attenuates Smad-specific gene responses and TGF-β-induced epithelial-mesenchymal transition. Thus, our results identify ADP-ribosylation of Smad proteins by PARP-1 as a key step in controlling the strength and duration of Smad-mediated transcription.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-128847 (URN)10.1016/j.molcel.2010.10.029 (DOI)000284988400006 ()21095583 (PubMedID)
Available from: 2010-07-28 Created: 2010-07-27 Last updated: 2017-12-12Bibliographically approved
2. TGFβ-mediated transcription is regulated by PARP-1/PARG-balanced ADP-ribosylation
Open this publication in new window or tab >>TGFβ-mediated transcription is regulated by PARP-1/PARG-balanced ADP-ribosylation
(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-128844 (URN)
Available from: 2010-07-27 Created: 2010-07-27 Last updated: 2010-08-23
3. 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, p. 655-662Article 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: 2017-12-13Bibliographically approved
4. 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

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