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Gudey, Shyam Kumar
Alternative names
Publications (10 of 13) Show all publications
Aripaka, K., Gudey, S. K., Zang, G., Schmidt, A., Åhrling, S. S., Österman, L., . . . Landström, M. (2019). TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer. EBioMedicine, 45, 192-207
Open this publication in new window or tab >>TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer
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2019 (English)In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed) Published
Abstract [en]

Background: Tumour necrosis factor receptor associated factor 6 (TRAF6) promotes inflammation in response to various cytokines. Aberrant Wnt3a signals promotes cancer progression through accumulation of β-Catenin. Here we investigated a potential role for TRAF6 in Wnt signaling.

Methods: TRAF6 expression was silenced by siRNA in human prostate cancer (PC3U) and human colorectal SW480 cells and by CRISPR/Cas9 in zebrafish. Several biochemical methods and analyses of mutant phenotype in zebrafish were used to analyse the function of TRAF6 in Wnt signaling.

Findings: Wnt3a-treatment promoted binding of TRAF6 to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-Catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. Database analysis revealed a correlation between TRAF6 mRNA and Wnt target genes in patients with prostate cancer, and high expression of LRP5, TRAF6 and c-Myc correlated with poor prognosis. By using CRISPR/Cas9 to silence TRAF6 in zebrafish, we confirm TRAF6 as a key molecule in Wnt3a signaling for expression of Wnt target genes.

Interpretation: We identify TRAF6 as an important component in Wnt3a signaling to promote activation of Wnt target genes, a finding important for understanding mechanisms driving prostate cancer progression.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
beta-Catenin, LRP5, Prostate cancer, TRAF6, Wnt3a, Zebrafish
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-161915 (URN)10.1016/j.ebiom.2019.06.046 (DOI)000475860000026 ()31262711 (PubMedID)2-s2.0-85067957867 (Scopus ID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-11-04Bibliographically approved
Gudey, S. K., Sundar, R., Heldin, C.-H., Bergh, A. & Landström, M. (2017). Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFβ stimulation in cancer. OncoTarget, 8(58), 97703-97726
Open this publication in new window or tab >>Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFβ stimulation in cancer
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 97703-97726Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor beta (TGF beta) is a key regulator of epithelial-tomesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGF beta, on EMT, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGF beta stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGF beta receptor I (T beta RI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, T beta RI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
signal transduction, tumor biology, Snail1, sumoylation, prostate cancer
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-144979 (URN)10.18632/oncotarget.20097 (DOI)000419392300002 ()29228645 (PubMedID)
Available from: 2018-02-20 Created: 2018-02-20 Last updated: 2019-05-09Bibliographically approved
Tyler, A., Johansson, A., Karlsson, T., Kumar Gudey, S., Brännström, T., Grankvist, K. & Behnam-Motlagh, P. (2015). Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells. Experimental Cell Research, 336(1), 23-32
Open this publication in new window or tab >>Targeting glucosylceramide synthase induction of cell surface globotriaosylceramide (Gb3) in acquired cisplatin-resistance of lung cancer and malignant pleural mesothelioma cells
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2015 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 336, no 1, p. 23-32Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Acquired resistance to cisplatin treatment is a caveat when treating patients with non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). Ceramide increases in response to chemotherapy, leading to proliferation arrest and apoptosis. However, a tumour stress activation of glucosylceramide synthase (GCS) follows to eliminate ceramide by formation of glycosphingolipids (GSLs) such as globotriaosylceramide (Gb3), the functional receptor of verotoxin-1. Ceramide elimination enhances cell proliferation and apoptosis blockade, thus stimulating tumor progression. GSLs transactivate multidrug resistance 1/P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1) expression which further prevents ceramide accumulation and stimulates drug efflux. We investigated the expression of Gb3, MDR1 and MRP1 in NSCLC and MPM cells with acquired cisplatin resistance, and if GCS activity or MDR1 pump inhibitors would reduce their expression and reverse cisplatin-resistance.

METHODS: Cell surface expression of Gb3, MDR1 and MRP1 and intracellular expression of MDR1 and MRP1 was analysed by flow cytometry and confocal microscopy on P31 MPM and H1299 NSCLC cells and subline cells with acquired cisplatin resistance. The effect of GCS inhibitor PPMP and MDR1 pump inhibitor cyclosporin A for 72h on expression and cisplatin cytotoxicity was tested.

RESULTS: The cisplatin-resistant cells expressed increased cell surface Gb3. Cell surface Gb3 expression of resistant cells was annihilated by PPMP whereas cyclosporin A decreased Gb3 and MDR1 expression in H1299 cells. No decrease of MDR1 by PPMP was noted in using flow cytometry, whereas a decrease of MDR1 in H1299 and H1299res was indicated with confocal microscopy. No certain co-localization of Gb3 and MDR1 was noted. PPMP, but not cyclosporin A, potentiated cisplatin cytotoxicity in all cells.

CONCLUSIONS: Cell surface Gb3 expression is a likely tumour biomarker for acquired cisplatin resistance of NSCLC and MPM cells. Tumour cell resistance to MDR1 inhibitors of cell surface MDR1 and Gb3 could explain the aggressiveness of NSCLC and MPM. Therapy with GCS activity inhibitors or toxin targeting of the Gb3 receptor may substantially reduce acquired cisplatin drug resistance of NSCLC and MPM cells.

Keywords
Cisplatin,  Glucosylceramide synthase (GCS),  Globotriaosylceramide (Gb3),  Lung cancer,  Multidrug resistance 1/P-glycoprotein (MDR1), Multidrug resistance-associated protein 1 (MRP1),  Malignant pleural mesothelioma (MPM),  DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP),  Cyclosporin A,  Acquired drug resistance
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:umu:diva-103786 (URN)10.1016/j.yexcr.2015.05.012 (DOI)000358821700003 ()26004871 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2015-05-30 Created: 2015-05-30 Last updated: 2018-06-07Bibliographically approved
Sundar, R., Gudey, S. K., Heldin, C.-H. & Landström, M. (2015). TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor. Cell Cycle, 14(4), 554-565
Open this publication in new window or tab >>TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor
2015 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 4, p. 554-565Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor (TGF) can act either as a tumor promoter or a tumor suppressor in a context-dependent manner. High levels of TGF are found in prostate cancer tissues and correlate with poor patient prognosis. We recently identified a novel TGF-regulated signaling cascade in which TGF type I receptor (TRI) is activated by the E3 ligase TNF-receptor-associated factor 6 (TRAF6) via the Lys63-linked polyubiquitination of TRI. TRAF6 also contributes to activation of TNF--converting enzyme and presenilin-1, resulting in the proteolytic cleavage of TRI and releasing the intracellular domain of TRI, which is translocated to the nucleus to promote tumor invasiveness. In this report, we provide evidence that Lys178 of TRI is polyubiquitinated by TRAF6. Moreover, our data suggest that TRAF6-mediated Lys63-linked ubiquitination of the TRI intracellular domain is a prerequisite for TGF regulation of mRNA for cyclin D1 (CCND1), expression, as well as for the regulation of other genes controlling the cell cycle, differentiation, and invasiveness of prostate cancer cells.

Place, publisher, year, edition, pages
Taylor & Francis, 2015
Keywords
cell cycle, cyclin D1, EMT, invasion, prostate cancer, Snail1, TRAF6, transforming growth factor beta
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-101605 (URN)10.4161/15384101.2014.990302 (DOI)000350137700018 ()25622187 (PubMedID)
Available from: 2015-04-13 Created: 2015-04-07 Last updated: 2018-06-07Bibliographically approved
Gudey, S. K., Wallenius, A. & Landström, M. (2014). Regulated intramembrane proteolysis of the TGF beta type I receptor conveys oncogenic signals. Future Oncology, 10(11), 1853-1861
Open this publication in new window or tab >>Regulated intramembrane proteolysis of the TGF beta type I receptor conveys oncogenic signals
2014 (English)In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 10, no 11, p. 1853-1861Article in journal (Refereed) Published
Abstract [en]

Cancer cells produce high levels of TGF beta, a multipotent cytokine. Binding of TGF beta to its cell surface receptors, the transmembrane serine/threonine kinases T beta RII and T beta RI, causes phosphorylation and activation of intracellular latent Smad transcription factors. Nuclear Smads act in concert with specific transcription factors to reprogram epithelial cells to become invasive mesenchymal cells. TGF beta also propagates non-canonical signals, so it is crucial to have a better understanding of the underlying molecular mechanisms which favor this pathway. Here we highlight our recent discovery that TGF beta promotes the proteolytic cleavage of T beta RI in cancer cells, resulting in the liberation and nuclear translocation of its intracellular domain, acting as co-regulator to transcribe pro-invasive genes. This newly identified oncogenic TGF beta pathway resembles the Notch signaling pathway. We discuss our findings in relation to Notch and provide a short overview of other growth factors that transduce signals via nuclear translocation of their cell surface receptors.

Place, publisher, year, edition, pages
London, UK: Future Medicine Ltd, 2014
Keywords
cancer, nucleus TGF beta, proteolysis, receptors, signal transduction
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-96974 (URN)10.2217/FON.14.45 (DOI)000344058100006 ()
Available from: 2014-12-09 Created: 2014-12-05 Last updated: 2018-06-07Bibliographically approved
Thakur, N., Gudey, S. K., Marcusson, A., Fu, J. Y., Bergh, A., Heldin, C.-H. & Landström, M. (2014). TGF beta-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1. Cell Cycle, 13(15), 2400-2414
Open this publication in new window or tab >>TGF beta-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail1
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2014 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 15, p. 2400-2414Article in journal (Refereed) Published
Abstract [en]

High levels of transforming growth factor-beta (TGF beta) correlate with poor prognosis for patients with prostate cancer and other cancers. TGF beta is a multifunctional cytokine and crucial regulator of cell fate, such as epithelial to mesenchymal transition (EMT), which is implicated in cancer invasion and progression. TGF beta conveys its signals upon binding to type I and type II serine/threonine kinase receptors (T beta RI/II); phosphorylation of Smad2 and Smad3 promotes their association with Smad4, which regulates expression of targets genes, such as Smad7, p21, and c-Jun. TGF beta also activates the ubiquitin ligase tumor necrosis factor receptor-associated factor 6 (TRAF6), which associates with T beta RI and activates the p38 mitogen-activated protein kinase (MAPK) pathway. Snail1 is a key transcription factor, induced by TGF beta that promotes migration and invasion of cancer cells. In this study, we have identified a novel binding site for c-Jun in the promoter of the Snail1 gene and report that the activation of the TGF beta-TRAF6-p38 MAPK pathway promotes both c-Jun expression and its activation via p38a-dependent phosphorylation of c-Jun at Ser63. The TRAF6-dependent activation of p38 also leads to increased stability of c-Jun, due to p38-dependent inactivation of glycogen synthase kinase (GSK) 3 beta by phosphorylation at Ser9. Thus, our findings elucidate a novel role for the p38 MAPK pathway in stimulated cells, leading to activation of c-Jun and its binding to the promoter of Snail1, thereby triggering motility and invasiveness of aggressive human prostate cancer cells.

Keywords
c-Jun, invasion, p38 MAPK, prostate cancer, Smads, Snail1, TGF beta, TRAF6
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-93495 (URN)10.4161/cc.29339 (DOI)000340720900016 ()
Available from: 2014-11-09 Created: 2014-09-23 Last updated: 2018-06-07Bibliographically approved
Gudey, S. K. (2014). TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>TRAF6 stimulates TGFβ-induced oncogenic signal transduction in cancer cells
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
TRAF6 stimulerar TGFβ-inducerad onkogen signal transduction i cancerceller.
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. p. 70
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1638
Keywords
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:nbn:se:umu:diva-87017 (URN)978-91-7601-025-9 (ISBN)
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: 2018-06-08Bibliographically approved
Gudey, S. K., Sundar, R., Mu, Y., Wallenius, A., Zang, G., Bergh, A., . . . Landström, M. (2014). TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1. Science Signaling, 7(307), Article ID ra2.
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, article id 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: 2018-06-08Bibliographically approved
Mu, Y., Gudey, S. K. & Landström, M. (2012). Non-Smad signaling pathways. Cell and Tissue Research, 347(1), 11-20
Open this publication in new window or tab >>Non-Smad signaling pathways
2012 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 347, no 1, p. 11-20Article, review/survey (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF beta) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGF beta signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (T beta RI and T beta RII, respectively). The activated T beta R complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGF beta also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGF beta-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGF beta-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGF beta are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGF beta-induced responses by non-Smad signaling pathways.

Keywords
Non-Smads, Smads, TAK1, TGF beta, TRAF6
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-52024 (URN)10.1007/s00441-011-1201-y (DOI)000298800700004 ()
Available from: 2012-02-29 Created: 2012-02-08 Last updated: 2018-06-08Bibliographically approved
Mu, Y., Sundar, R., Thakur, N., Ekman, M., Gudey, S. K., Yakymovych, M., . . . Landström, M. (2011). TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer. Nature Communications, 2(330), 11
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, p. 11-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: 2018-06-08Bibliographically approved
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