uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Molecular mechanisms for activation of non-canonical TGFβ pathways and their importance during prostate cancer progression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is the most common invasive cancer diagnosed in men and a major and growing health problem in Western countries. Deregulation of different pathways has been implicated in progression of prostate cancer, namely nuclear factor kappa enhancer binding protein (NF-κB), transforming growth factor β (TGFβ), phosphoinositide 3ʹ-kinase/AKT (PI3K/AKT) and Src kinase pathways. However, the detailed mechanisms by which TGFβ activates these pathways to contribute in tumorigenesis and invasive behavior of prostate cancer cells have not been elucidated.

We have demonstrated (paper I) that the E3 ligase activity of TRAF6 is crucial for recruitment of the regulatory subunit of PI3K, p85α, to TβRI and for TGFβ-induced Lys63-linked polyubiquitination of p85α. TRAF6 is required for the TGFβ-induced recruitment of AKT to the complex of PI3K and TβRI, where the polyubiquitination and activation of AKT occurs. When activated, AKT promotes TGFβ-induced cell migration which is dependent on p85 and PI3K activity, as well as on TRAF6, but not on TβRI kinase activity. Thus, TGFβ-induced activation of PI3K/AKT induces cell motility contributing to the progression of cancer.

We have demonstrated (paper II) a pivotal role of TAK1 polyubiquitination in three different pathways, including TNFR, IL-1R, and TLR4 signaling. Lys63-linked polyubiquitination of TAK1 at Lys34 is essential for downstream signaling to NF-κB-mediated target gene expression in both cancer and immune cells. These findings are of importance for the understanding of the mechanism of activation of NF-κB in inflammation and may aid in the development of new therapeutic strategies to treat chronic inflammation and cancer.

We have also shown (paper III) that TGFβ activates the tyrosine kinase Src via formation of a complex between TβRI and Src. The E3 ligase TRAF6 promotes the formation of the complex in a manner not dependent on its ubiquitin ligase activity, suggesting that TRAF6 acts as an adaptor. Moreover, the activation of Src is not dependent on the kinase activity of TβRI. On a functional level, Src activity was found to be necessary for TGFβ-induced chemotaxis.

In conclusion, we have elucidated molecular mechanisms whereby TGFβ activates non-Smad pathways, i.e. PI3K and Src. Our findings shed light on the pro-tumorigenesis mechanisms of TGFβ. In addition, we have demonstrated how the activation of TAK1, an important component of the TGFβ non-Smad pathway, by TGFβ and other stimuli leads to the activation of NF-κB and thereby induction of inflammation which likely contributes to prostate cancer progression.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1126
Keyword [en]
TGFβ, AKT, PI3K, p85α, TRAF6, TAK1, NF-κB, Src, prostate cancer, PC-3U, cell migration, inflammation
National Category
Medical and Health Sciences
Research subject
Biology with specialization in Molecular Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-259224ISBN: 978-91-554-9301-1 (print)OAI: oai:DiVA.org:uu-259224DiVA: diva2:844384
Public defence
2015-10-01, B42, Entrance A11, Husargatan 3, Biomedicinskt Centrum, 75124, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-09-10 Created: 2015-07-30 Last updated: 2015-10-01
List of papers
1. TGFβ promotes cancer cell migration via TRAF6-specific ubiquitination of p85α causing activation of the PI3K/AKT pathway
Open this publication in new window or tab >>TGFβ promotes cancer cell migration via TRAF6-specific ubiquitination of p85α causing activation of the PI3K/AKT pathway
Show others...
(English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145Article in journal (Refereed) Submitted
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-259222 (URN)
Available from: 2015-07-30 Created: 2015-07-30 Last updated: 2017-12-04
2. Polyubiquitination of transforming growth factor β (TGFβ)-associated kinase 1 mediates nuclear factor-κB activation in response to different inflammatory stimuli
Open this publication in new window or tab >>Polyubiquitination of transforming growth factor β (TGFβ)-associated kinase 1 mediates nuclear factor-κB activation in response to different inflammatory stimuli
Show others...
2012 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 1, 123-133 p.Article in journal (Refereed) Published
Abstract [en]

The transcription factor nuclear factor κB (NF-κB) plays a central role in regulating inflammation in response to several external signals. The TGFβ-associated kinase 1 (TAK1) is an upstream regulator of NF-κB signaling. In TGFβ-stimulated cells, TAK1 undergoes Lys-63-linked polyubiquitination at Lys-34 by TNF receptor-associated factor 6 and is thereby activated. The aim of this study was to investigate whether TAK1 polyubiquitination at Lys-34 is also essential for NF-κB activation via TNF receptor, IL-1 receptor and toll-like receptor 4. We observed that TAK1 polyubiquitination occurred at Lys-34 and required the E3 ubiquitin ligase TNF receptor-associated factor 6 after stimulation of cells with IL-1β. Polyubiquitination of TAK1 also occurred at Lys-34 in cells stimulated by TNF-α and LPS, which activates TLR4, as well as in HepG2 and prostate cancer cells stimulated with TGFβ, which in all cases resulted in NF-κB activation. Expression of a K34R-mutant TAK1 led to a reduced NF-κB activation, IL-6 promoter activity, and proinflammatory cytokine secretion by TNF-α-stimulated PC-3U cells. Similar results were obtained in the mouse macrophage cell line RAW264.7 after LPS treatment. In conclusion, polyubiquitination of TAK1 is correlated with activation of TAK1 and is essential for activation of NF-κB signaling downstream of several receptors.

Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology, Inc., 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168812 (URN)10.1074/jbc.M111.285122 (DOI)000298682400015 ()22069318 (PubMedID)
Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2017-12-07
3. Mechanism of regulation of Src kinase by transforming growth factor ß
Open this publication in new window or tab >>Mechanism of regulation of Src kinase by transforming growth factor ß
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-254732 (URN)
Available from: 2015-06-10 Created: 2015-06-10 Last updated: 2015-10-01

Open Access in DiVA

fulltext(1217 kB)111 downloads
File information
File name FULLTEXT01.pdfFile size 1217 kBChecksum SHA-512
1ca6767641f959b2d515754e169b361835a8c92fde0dceb09b0f894a7cf52e12d48ee9a83a089a915e4ad451b9464381ab3f29034905b57eadf4672b1b27bf02
Type fulltextMimetype application/pdf
Buy this publication >>

Authority records BETA

Hamidi, Anahita

Search in DiVA

By author/editor
Hamidi, Anahita
By organisation
Ludwig Institute for Cancer Research
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
Total: 111 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 859 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf