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TGFβ induces SIK to negatively regulate type I receptor kinase signaling
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
Vise andre og tillknytning
2008 (engelsk)Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 182, nr 4, s. 655-662Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
The Rockefeller University Press , 2008. Vol. 182, nr 4, s. 655-662
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-103239DOI: 10.1083/jcb.200804107ISI: 000259050000007PubMedID: 18725536OAI: oai:DiVA.org:uu-103239DiVA, id: diva2:217768
Tilgjengelig fra: 2009-05-15 Laget: 2009-05-15 Sist oppdatert: 2017-12-13bibliografisk kontrollert
Inngår i avhandling
1. Regulation of TGF-β Signaling by Post-Translational Modifications
Åpne denne publikasjonen i ny fane eller vindu >>Regulation of TGF-β Signaling by Post-Translational Modifications
2010 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2010. s. 59
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 577
Emneord
TGF-β, Smad, PARP-1, PARG, ALK5, SIK, signal transduction, transcription, post-translational modification, phosphorylation, ubiquitin, ADP-ribosylation, DNA-binding, receptor degradation
HSV kategori
Forskningsprogram
Biologi med inriktning mot molekylär cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-128855 (URN)978-91-554-7844-5 (ISBN)
Disputas
2010-09-10, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2010-08-20 Laget: 2010-07-27 Sist oppdatert: 2010-08-30bibliografisk kontrollert
2. Diversification of TGF-β Signaling in Homeostasis and Disease
Åpne denne publikasjonen i ny fane eller vindu >>Diversification of TGF-β Signaling in Homeostasis and Disease
2011 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2011. s. 77
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 679
Emneord
TGF-β, signaling, SIK, EMT, polarity, Notch, ALK5, p21, growth arrest, Smurf, Smad7, receptor, SNF1LK
HSV kategori
Forskningsprogram
Biologi med inriktning mot molekylär cellbiologi
Identifikatorer
urn:nbn:se:uu:diva-152267 (URN)978-91-554-8098-1 (ISBN)
Disputas
2011-06-11, Room B42, BMC, Husargatan 3, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2011-05-20 Laget: 2011-04-27 Sist oppdatert: 2018-06-26bibliografisk kontrollert

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