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TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells
Umeå University, Faculty of Medicine, Department of Medical Biosciences. (Marene Landstrom Group)ORCID iD: K-8186-2013
2014 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
TRAF6 stimulerar TGFβ-inducerad onkogen signal transduction i cancerceller. (Swedish)
Abstract [en]

Prostate cancer is one of the leading causes of cancer-related deaths in men worldwide, with 10,000 new cases/year diagnosed in Sweden. In this context, there is an urgent need to identify new biomarkers to detect prostate cancer at an initial stage for earlier treatment intervention. Although how prostate cancer develops has not been fully established, the male sex hormone testosterone is a known prerequisite for prostate cancer development. High levels of transforming growth factor-β (TGFβ) are prognostically unfavorable in prostate cancer patients.

TGFβ is a multifunctional cytokine that regulates a broad range of cellular responses. TGFβ signals through either the canonical Smad or the non-Smad signaling cascade. Cancerous cells develop different strategies to evade defense mechanisms and metastasize to different parts of the body. This thesis unveils one such novel mechanism related to TGFβ signaling.

The first two articles provide evidence that TGFβ receptor type I (TβRI) is ubiquitinated by tumor necrosis factor receptor-associated factor 6 (TRAF6) and is cleaved at the ectodomain region by tumor necrosis factor alpha converting enzyme (TACE) in a protein kinase C zeta type-dependent manner. After TβRI is shed from the ectodomain, it undergoes a second cleavage by presenilin 1 (PS1), a γ-secretase catalytic subunit, which liberates the TβRI intracellular domain (TβRI-ICD) from the cell membrane. TRAF6 promotes TGFβ-dependent Lys63-linked polyubiquitination and recruitment of PS1 to the TβRI complex, and facilitates the cleavage of TβRI by PS1 to generate a TβRI-ICD. The TβRI-ICD then translocates to the nucleus, where it binds with the transcriptional co-activator p300 and regulates the transcription of pro-invasive target genes such as Snail1. Moreover, the nuclear translocated TβRI-ICD cooperates with the Notch intracellular domain (NICD), a core component in the Notch signaling pathway, to drive the expression of invasive genes. Interestingly, treatment with g-secretase inhibitors was able to inhibit cleavage of TβRI and inhibit the TGFβ-induced oncogenic pathway in an in vivo prostate cancer xenograft model.

In the third article, we identified that Lysine 178 is the acceptor lysine in TβRI that is ubiquitinated by TRAF6. The TβRI K178R mutant was neither ubiquitinated nor translocated to the nucleus, and prevented transcriptional regulation of invasive genes in a dominant negative manner.

In the fourth article, we show that TGFβ utilizes the E3-ligase TRAF6 and the p38 mitogen-activated protein kinase to phosphorylate c-Jun. In turn, the phosphorylated c-Jun activates p21 and Snail1 in a non-canonical Smad-independent pathway, and thereby promotes invasion in cancerous cells.

In summary, we elucidate a new mechanism of TGFβ-induced oncogenic signal transduction in cancer cells in which TRAF6 plays a fundamental role. This opens a new avenue in the field of TGFβ signaling.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2014. , 70 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1638
Keyword [en]
c-Jun, invasion, non-Smad, Notch, NICD, oncogenesis, presenilin1, PKCζ, prostate cancer, p21, p38, p300, Snail1, TGFβ, TβRI, TACE, TRAF6, ubiquitination, TGFbeta signal transduction
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-87017ISBN: 978-91-7601-025-9 (print)OAI: oai:DiVA.org:umu-87017DiVA: diva2:705868
Public defence
2014-04-11, Hörsal E 04, Unod R1, Norrlands universitetssjukhus, Umeå, 10:15 (English)
Opponent
Supervisors
Funder
Swedish Cancer SocietySwedish Research Council
Available from: 2014-03-19 Created: 2014-03-18 Last updated: 2014-03-19Bibliographically approved
List of papers
1. TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer
Open this publication in new window or tab >>TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer
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2011 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, no 330, 11- p.Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGF beta binding to type II and type I serine/threonine kinase receptors (T beta RII and T beta RI) causes activation of different intracellular signaling pathways. T beta RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGF beta, via TRAF6, causes Lys63-linked polyubiquitination of T beta RI, promoting cleavage of T beta RI by TNF-alpha converting enzyme (TACE), in a PKC zeta-dependent manner. The liberated intracellular domain (ICD) of T beta RI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGF beta-induced invasion of cancer cells is TACE- and PKC zeta-dependent and the T beta RI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for T beta RI in TGF beta mediated tumour invasion.

Place, publisher, year, edition, pages
London: Nature Publishing Group, 2011
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-47676 (URN)10.1038/ncomms1332 (DOI)000294802600035 ()
Available from: 2011-10-03 Created: 2011-09-27 Last updated: 2017-12-08Bibliographically approved
2. TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
Open this publication in new window or tab >>TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
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2014 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, ra2Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2014
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-85774 (URN)10.1126/scisignal.2004207 (DOI)000329401100004 ()
Funder
Swedish Research Council, K2010-67X-15284-01-3Swedish Cancer Society, 100303Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2014-02-13 Created: 2014-02-10 Last updated: 2017-12-06Bibliographically approved
3. Identification of Lys178 as the acceptor lysine of TGF-beta type I receptor poly-ubiquitination.
Open this publication in new window or tab >>Identification of Lys178 as the acceptor lysine of TGF-beta type I receptor poly-ubiquitination.
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-87057 (URN)
Available from: 2014-03-18 Created: 2014-03-18 Last updated: 2014-03-19Bibliographically approved
4. TGFβ engages TRAF6 and p38 to regulate c-Jun activity and invasion of prostate cancer cells.
Open this publication in new window or tab >>TGFβ engages TRAF6 and p38 to regulate c-Jun activity and invasion of prostate cancer cells.
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-87058 (URN)
Available from: 2014-03-18 Created: 2014-03-18 Last updated: 2014-03-19Bibliographically approved

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