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  • 1.
    Aripaka, Karthik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schmidt, Alexej
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Åhrling, Samaneh Shabani
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Österman, Lennart
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    von Hofsten, Jonas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM). Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TRAF6 function as a novel co-regulator of Wnt3a target genes in prostate cancer2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 45, p. 192-207Article in journal (Refereed)
    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.

  • 2.
    Bugaytsova, Jeanna A.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Björnham, Oscar
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics. Swedish Defence Research Agency, 906 21 Umeå, Sweden.
    Chernov, Yevgen A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gideonsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Henriksson, Sara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mendez, Melissa
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sjöström, Rolf
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mahdavi, Jafar
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. School of Life Sciences, CBS, University of Nottingham, NG7 2RD Nottingham, UK.
    Shevtsova, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ilver, Dag
    Moonens, Kristof
    Quintana-Hayashi, Macarena P.
    Moskalenko, Roman
    Aisenbrey, Christopher
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Bylund, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Schmidt, Alexej
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Åberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Koeniger, Verena
    Vikström, Susanne
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rakhimova, Lena
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ögren, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Liu, Hui
    Goldman, Matthew D.
    Whitmire, Jeannette M.
    Åden, Jörgen
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Younson, Justine
    Kelly, Charles G.
    Gilman, Robert H.
    Chowdhury, Abhijit
    Mukhopadhyay, Asish K.
    Nair, G. Balakrish
    Papadakos, Konstantinos S.
    Martinez-Gonzalez, Beatriz
    Sgouras, Dionyssios N.
    Engstrand, Lars
    Unemo, Magnus
    Danielsson, Dan
    Suerbaum, Sebastian
    Oscarson, Stefan
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Holgersson, Jan
    Esberg, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Strömberg, Nicklas
    Umeå University, Faculty of Medicine, Department of Odontology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Eldridge, Angela M.
    Chromy, Brett A.
    Hansen, Lori M.
    Solnick, Jay V.
    Linden, Sara K.
    Haas, Rainer
    Dubois, Andre
    Merrell, D. Scott
    Schedin, Staffan
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Remaut, Han
    Arnqvist, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Berg, Douglas E.
    Boren, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence2017In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 21, no 3, p. 376-389Article in journal (Refereed)
    Abstract [en]

    The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.

  • 3. Ekman, Maria
    et al.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lee, So Young
    Edlund, Sofia
    Kozakai, Takaharu
    Thakur, Noopur
    Tran, Hoanh
    Qian, Jiang
    Groeden, Joanna
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    APC and Smad7 link TGF beta type I receptors to the microtubule system to promote cell migration2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed)
    Abstract [en]

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

  • 4.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFβ stimulation in cancer2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 58, p. 97703-97726Article in journal (Refereed)
    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.

  • 5.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Pro-invasive Snail1 targets TGFbeta receptor I to promote epithelial to mesenchymal transition in prostate cancerManuscript (preprint) (Other academic)
  • 6.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University.
    TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 12014In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, article id ra2Article in journal (Refereed)
    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.

  • 7.
    Gudey, Shyam Kumar
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wallenius, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Regulated intramembrane proteolysis of the TGF beta type I receptor conveys oncogenic signals2014In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 10, no 11, p. 1853-1861Article in journal (Refereed)
    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.

  • 8. Hamidi, Anahita
    et al.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thakur, Noopur
    Itoh, Susumu
    Marcusson, Anders
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, article id eaal4186Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor–β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3′-kinase (PI3K)–protein kinase B (AKT) pathway. We found that TGF-β activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85α and promoted the formation of a complex between the TGF-β type I receptor (TβRI) and p85α, which led to the activation of PI3K and AKT. Lys63-linked polyubiquitylation of p85α on Lys513 and Lys519 in the iSH2 (inter–Src homology 2) domain was required for TGF-β–induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TβRI. In situ proximity ligation assays revealed that polyubiquitylation of p85α was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-β activates the PI3K-AKT pathway to drive cell migration.

  • 9.
    Hamidi, Anahita
    et al.
    Ludwig Institute for Cancer Research, Uppsala University.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Thakur, Noopur
    Marcusson, Anders
    Ludwig Institute for Cancer Research.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    TGFβ promotes prostate cancer cell migration via TRAF6-mediated ubiquitination of p85α causing activation of the PI3K/AKT pathway.In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145Article in journal (Other academic)
  • 10. Hamidi, Anahita
    et al.
    von Bulow, Verena
    Hamidi, Rosita
    Winssinger, Nicolas
    Barluenga, Sofia
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Polyubiquitination of Transforming Growth Factor beta (TGF beta)-associated Kinase 1 Mediates Nuclear Factor-kappa B Activation in Response to Different Inflammatory Stimuli2012In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, no 1, p. 123-133Article in journal (Refereed)
    Abstract [en]

    The transcription factor nuclear factor kappa B (NF-kappa B) plays a central role in regulating inflammation in response to several external signals. The TGF beta-associated kinase 1 (TAK1) is an upstream regulator of NF-kappa B signaling. In TGF beta-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-kappa B 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-1 beta. Polyubiquitination of TAK1 also occurred at Lys-34 in cells stimulated by TNF-alpha and LPS, which activates TLR4, as well as in HepG2 and prostate cancer cells stimulated with TGF beta, which in all cases resulted in NF-kappa B activation. Expression of a K34R-mutant TAK1 led to a reduced NF-kappa B activation, IL-6 promoter activity, and proinflammatory cytokine secretion by TNF-alpha-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-kappa B signaling downstream of several receptors.

  • 11. Heldin, Carl-Henrik
    et al.
    Landström, Maréne
    Ludwig Institute for Cancer Research, Uppsala University.
    Moustakas, Aristidis
    Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition2009In: Current Opinion in Cell Biology, ISSN 0955-0674, E-ISSN 1879-0410, Vol. 21, no 2, p. 166-176Article in journal (Refereed)
    Abstract [en]

    Members of the transforming growth factor-beta (TGF-beta) family have important roles during embryogenesis, as well as in the control of tissue homeostasis in the adult. They exert their cellular effects via binding to serine/threonine kinase receptors. Members of the Smad family of transcription factors are important intracellular messengers, and recent studies have shown that the ubiquitin ligase TRAF6 mediates other specific signals. TGF-beta signaling is tightly controlled by post-translational modifications, which regulate the activity, stability, and subcellular localization of the signaling components. The aim of this review is to summarize some of the recent findings on the mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition.

  • 12.
    Holst, Mikkel Roland
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Vidal-Quadras, Maite
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Larsson, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hubert, Madlen
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Blomberg, Jeanette
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Lundborg, Magnus
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 20, no 8, p. 1893-1905Article in journal (Refereed)
    Abstract [en]

    Cellular blebbing, caused by local alterations in cellsurface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrinindependent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension- mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol- interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

  • 13.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Att upptäcka och bedöma cancer2013In: Cancerforskning på nya vägar: en bok från Forskningens dag 2013, Medicinska fakulteten vid Umeå universitet / [ed] Mattias Grundström Mitz och Lena Åminne, Umeå: Umeå universitet , 2013, 1, p. 23-35Chapter in book (Other (popular science, discussion, etc.))
  • 14.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The role of transforming growth factor beta signalling pathways in tumour biology2012In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, p. S4-S4Article in journal (Refereed)
  • 15.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The TAK1-TRAF6 signalling pathway2010In: International Journal of Biochemistry and Cell Biology, ISSN 1357-2725, E-ISSN 1878-5875, Vol. 42, no 5, p. 585-589Article in journal (Refereed)
    Abstract [en]

    Cellular responses to pathogens, growth factors, cytokines, extra- or intra-cellular stress, is a prerequisite for the cell to adapt to novel and potentially dangerous situations. If the changes in the extra- or intra-cellular milieu causes DNA-damage or revoke a signalling pathway utilized during morphogenesis, the epithelial cells might be forced to undergo programmed cell death (apoptosis) in the benefit for the whole organism or transform to a mesenchymal cell type (epithelial to mesenchymal transition; EMT), in respond to a specific stimuli. An overview is presented over the current knowledge for the key components in signal transduction in homeostasis, inflammation and cancer. A handful of transcription factors are crucial for the determination of the specific cellular responses, where the transforming growth factor-beta (TGF-beta) is an important factor as discussed in this review.

  • 16.
    Landström, Maréne
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TRAF62012In: Encyclopedia of Signaling Molecules / [ed] Sangdun Choi, New York: Springer-Verlag New York, 2012, p. 1916-1921Chapter in book (Refereed)
  • 17.
    Mallikarjuna, Pramod
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aripaka, Karthik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Interactions between TGF-β type I receptor and hypoxia-inducible factor-alpha mediates a synergistic crosstalk leading to poor prognosis for patients with clear cell renal cell carcinoma2019In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 18, no 17, p. 2141-2156Article in journal (Refereed)
    Abstract [en]

    To investigate the significance of expression of HIF-1 alpha, HIF-2 alpha, and SNAIL1 proteins; and TGF-beta signaling pathway proteins in ccRCC, their relation with clinicopathological parameters and patient's survival were examined. We also investigated potential crosstalk between HIF-alpha and TGF-beta signaling pathway, including the TGF-beta type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD). Tissue samples from 154 ccRCC patients and comparable adjacent kidney cortex samples from 38 patients were analyzed for HIF-1 alpha/2 alpha, TGF-beta signaling components, and SNAIL1 proteins by immunoblot. Protein expression of HIF-1 alpha and HIF-2 alpha were significantly higher, while SNAIL1 had similar expression levels in ccRCC compared with the kidney cortex. HIF-2 alpha associated with poor cancer-specific survival, while HIF-1 alpha and SNAIL1 did not associate with survival. Moreover, HIF-2 alpha positively correlated with ALK5-ICD, pSMAD2/3, and PAI-1; HIF-1 alpha positively correlated with pSMAD2/3; SNAIL1 positively correlated with ALK5-FL, ALK5-ICD, pSMAD2/3, PAI-1, and HIF-2 alpha. Intriguingly, in vitro experiments performed under normoxic conditions revealed that ALK5 interacts with HIF-1 alpha and HIF-2 alpha, and promotes their expression and the expression of their target genes GLUT1 and CA9, in a VHL dependent manner. We found that ALK5 induces expression of HIF-1 alpha and HIF-2 alpha, through its kinase activity. Under hypoxic conditions, HIF-alpha proteins correlated with the activated TGF-beta signaling pathway. In conclusion, we reveal that ALK5 plays a pivotal role in synergistic crosstalk between TGF-beta signaling and hypoxia pathway, and that the interaction between ALK5 and HIF-alpha contributes to tumor progression.

  • 18.
    Mallikarjuna, Pramod
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    VHL status regulates transforming growth factor-β signaling pathways in renal cell carcinoma2018In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, no 23, p. 16297-16310Article in journal (Refereed)
    Abstract [en]

    To evaluate the role of pVHL in the regulation of TGF-β signaling pathways in clear cell renal cell carcinoma (ccRCC) as well as in non-ccRCC; the expression of pVHL, and the TGF-β pathway components and their association with clinicopathological parameters and patient’s survival were explored. Tissue samples from 143 ccRCC and 58 non-ccRCC patients were examined by immunoblot. ccRCC cell lines were utilized for mechanistic in-vitro studies. Expression levels of pVHL were significantly lower in ccRCC compared with non-ccRCC. Non-ccRCC and ccRCC pVHL-High expressed similar levels of pVHL. Expression of the TGF-β type I receptor (ALK5) and intra-cellular domain were significantly higher in ccRCC compared with non-ccRCC. In non-ccRCC, expressions of ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 had no association with clinicopathological parameters and survival. In ccRCC pVHL-Low, ALK5-FL, ALK5-ICD, pSMAD2/3, and PAI-1 were significantly related with tumor stage, size, and survival. In ccRCC pVHL-High, the expression of PAI-1 was associated with stage and survival. In-vitro studies revealed that pVHL interacted with ALK5 to downregulate its expression through K48-linked poly-ubiquitination and proteasomal degradation, thus negatively controlling TGF-β induced cancer cell invasiveness. The pVHL status controls the ALK5 and can thereby regulate the TGF-β pathway, aggressiveness of tumors, and survival of the ccRCC and non-ccRCC patients.

  • 19.
    Mu, Yabing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Non-Smad signaling pathways2012In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 347, no 1, p. 11-20Article, review/survey (Refereed)
    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.

  • 20.
    Mu, Yabing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gao, Linlin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gahman, Timothy
    Ludwig Institute for Cancer Research, La Jolla.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGFβ-induced activation of PKCζ confers invasive prostate cancer growthManuscript (preprint) (Other academic)
    Abstract [en]

    One of the hallmarks for aggressivecancer is the capability oftumor cells to become invasive and metastatic. Cancer cells and tumor stromal cells oftenproduce high levels of transforming growth factor b(TGFb) which initiates intracellular signaling pathways in cancer cells in a contextualdependentmanner. Atypical protein kinase C z(PKCz) is a multifunctional protein which maintains cell polarity of normal epithelial cells, while itsaberrantexpression and activation is linked to tumor progression. Tumor necrosisfactor receptor-associated factor6 (TRAF6) is amplified in lung cancer and caninitiate intracellular oncogenic signals. In prostate cancer cellsTRAF6 promotesligand-induced proteolytic cleavage of TGFbtype I receptor(TbRI), and nuclear translocation of its intracellular domain (ICD) to confer invasion of cancer cells. Here we report our novel findingsthat PKCzharboursa TRAF6 consensus binding site and that TRAF6 causes Lys63-linked polyubiquitination of PKCz. TGFb-induced phosphorylationof PKCzis dependent on TRAF6in prostate cancer cells and we have investigated the potential usefulness of twodifferent inhibitors of PKCzas potential novel anti-cancer drugs.

  • 21.
    Mu, Yabing
    et al.
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Sundar, Reshma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Thakur, Noopur
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Ekman, Maria
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences. Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Yakymovych, Mariya
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Hermansson, Annika
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Dimitriou, Helen
    Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala, Sweden.
    Bengoechea-Alonso, Maria Teresa
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Ericsson, Johan
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer2011In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 2, no 330, p. 11-Article in journal (Refereed)
    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.

  • 22.
    Mu, Yabing
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Engstrom, U.
    Busch, C.
    Landstrom, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGF beta-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 7, p. 1223-1231Article in journal (Refereed)
    Abstract [en]

    Background:

    The Par complex - comprising partition-defective 6 (Par6), Par3, and atypical protein kinase C (aPKC) - is crucial for cell polarisation, the loss of which contributes to cancer progression. Transforming growth factor beta (TGF beta)-induced phosphorylation of Par6 on the conserved serine 345 is implicated in epithelial-to-mesenchymal transition (EMT) in breast cancer. Here we investigated the importance of phosphorylated Par6 in prostate cancer.

    Methods:

    We generated a p-Par6(345)-specific antibody and verified its specificity in vitro. Endogenous p-Par6(345) was analysed by immunoblotting in normal human prostate RWPE1 and prostate cancer (PC-3U) cells. Subcellular localisation of p-Par6(345) in migrating TGF beta-treated PC-3U cells was analysed by confocal imaging. Invasion assays of TGF beta-treated PC-3U cells were performed. p-Par6 expression was immunohistochemically analysed in prostate cancer tissues.

    Results:

    TGF beta induced Par6 phosphorylation on Ser345 and its recruitment to the leading edge of the membrane ruffle in migrating PC-3U cells, where it colocalised with aPKC zeta. The p-Par6-aPKC zeta complex is important for cell migration and invasion, as interference with this complex prevented prostate cancer cell invasion. High levels of activated Par6 correlated with aggressive prostate cancer.

    Conclusions: Increased p-Par6Ser(345) levels in aggressive prostate cancer tissues and cells suggest that it could be a useful novel biomarker for predicting prostate cancer progression.

  • 23. Song, Jie
    et al.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    TGFβ activates PI3K-AKT signaling via TRAF62017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99205-99206Article in journal (Other academic)
  • 24.
    Song, Jie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Chunyan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGFb type I receptor and endosomal APPL regulate AURKB during mitosis and cytokinesisManuscript (preprint) (Other academic)
    Abstract [en]

    The cytokine transforming growth factor b(TGFb) suppressescell proliferationand promotesapoptosis1. It signalsvia specific serine/threonine kinase receptors, i.e.TGFbtype I (TbRI) and type II (TbRII) receptors2,3,causing growth arrest of normal epithelial cells. However, TGFbis often overexpressed inadvanced cancers,and promotes proliferation of tumour cells and their invasion. The intracellular domain (ICD) of TbRI is cleaved offin cancer cells,and is translocated to the nucleus in an APPL1/2-dependent manner, drivingan invasiveness program4.The specific mechanism(s) whereby cancer cells escape pro-apoptotic signals induced by TGFbremainspoorly understood. Here, we report that TbRI and APPL1/2 proteins orchestrate this escape via the pro-survival protein survivin and Aurora kinase B (AURKB), a key regulatorof mitosis and chromosomal stability5. We show that TbRI and APPL1/2 control expression of AURKB and that TbRI-ICDand AURKB form a complex during the telophase in PC-3Uprostate cancerand KELLY neuroblastomacells. APPL1/2 and TbRI also form a complex with survivin, a pro-survival protein. The identified TbRI–AURKB-survivinpathwayrepresents a novel function for TbRI to promote survival and cell division of cancer cells.

  • 25.
    Song, Jie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Chunyan
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Miaczynska, Marta
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 279-292Article in journal (Refereed)
    Abstract [en]

    The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

  • 26.
    Sorrentino, Alessandro
    et al.
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Thakur, Noopur
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Grimsby, Susanne
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Marcusson, Anders
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    von Bulow, Verena
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Schuster, Norbert
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Zhang, Shouting
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Heldin, Carl-Henrik
    1.Ludwig Institute for Cancer Research, Rudbeck Laboratory, Uppsala University, Sweden.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner2008In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 10, no 10, p. 1199-1207Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-beta signals through its Type II and Type I receptors (TbetaRII and TbetaRI) causing phosphorylation of Smad proteins. TGF-beta-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-beta-induced p38 activation. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TbetaRI. The TbetaRI-TRAF6 interaction is required for TGF-beta-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1-p38/JNK pathway, which leads to apoptosis. TbetaRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of TbetaRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

  • 27.
    Sundar, Reshma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Identification of Lys178 as the acceptor lysine of TGF-beta type I receptor poly-ubiquitination.Manuscript (preprint) (Other academic)
  • 28.
    Sundar, Reshma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TRAF6 promotes TGF beta-induced invasion and cell-cycle regulation via Lys63-linked polyubiquitination of Lys178 in TGF beta type I receptor2015In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 14, no 4, p. 554-565Article in journal (Refereed)
    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.

  • 29.
    Thakur, Noopur
    et al.
    Ludwig Institute for Cancer Research, Uppsala university.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Marcusson, Anders
    Ludwig Institute for Cancer Research, Uppsala university.
    Fu, Jing Ji
    Uppsala University.
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    TGFβ engages TRAF6 and p38 to regulate c-Jun activity and invasion of prostate cancer cells.Manuscript (preprint) (Other academic)
  • 30.
    Thakur, Noopur
    et al.
    Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Uppsala, Sweden.
    Gudey, Shyam Kumar
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Marcusson, Anders
    Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Uppsala, Sweden.
    Fu, Jing Yi
    Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    Uppsala Univ, Sci Life Lab, Ludwig Inst Canc Res, Uppsala, Sweden.
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGF beta-induced invasion of prostate cancer cells is promoted by c-Jun-dependent transcriptional activation of Snail12014In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 13, no 15, p. 2400-2414Article in journal (Refereed)
    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.

  • 31.
    Thakur, Noopur
    et al.
    Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Sorrentino, Alessandro
    Ludwig Institute for Cancer Research, Uppsala University, Sweden.
    Heldin, Carl-Henrik
    Ludwig Institute for Cancer Research, Uppsala University, Uppsala, Sweden.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TGF-beta uses the E3-ligase TRAF6 to turn on the kinase TAK1 to kill prostate cancer cells2009In: Future oncology (London, England), ISSN 1744-8301, Vol. 5, no 1, p. 1-3Article in journal (Refereed)
  • 32.
    Tumkur Sitaram, Raviprakash
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Medical Biosciences.
    Mallikarjuna, Pramod
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Transforming growth factor-β promotes aggressiveness and invasion of clear cell renal cell carcinoma2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 35917-35931Article in journal (Refereed)
    Abstract [en]

    The molecular mechanisms whereby transforming growth factor-β (TGF-β) promotes clear cell renal cell carcinoma (ccRCC) progression is elusive. The cell membrane bound TGF-β type I receptor (ALK5), was recently found to undergo proteolytic cleavage in aggressive prostate cancer cells, resulting in liberation and subsequent nuclear translocation of its intracellular domain (ICD), suggesting that ALK5-ICD might be a useful cancer biomarker. Herein, the possible correlation between ALK5 full length (ALK5-FL) and ALK5-ICD protein, phosphorylated Smad2/3 (pSmad2/3), and expression of TGF-β target gene PAI-1, was investigated in a clinical ccRCC material, in relation to tumor grade, stage, size and cancer specific survival. Expression of ALK5-FL, ALK5-ICD, pSmad2/3 and PAI-1 protein levels were significantly higher in higher stage and associated with adverse survival. ALK5-ICD, pSmad2/3 and PAI-1 correlated with higher grade, and ALK5-FL, pSmad2/3 and PAI-1 protein levels were significantly correlated with larger tumor size. Moreover, the functional role of the TGF-β - ALK5-ICD pathway were investigated in two ccRCC cell lines by treatment with ADAM/MMP2 inhibitor TAPI-2, which prevented TGF-β-induced ALK5-ICD generation, nuclear translocation, as well as cell invasion. The present study demonstrated that canonical TGF-β Smad2/3 pathway and generation of ALK5-ICD correlates with poor survival and invasion of ccRCC in vitro.

  • 33. Yakymovych, Ihor
    et al.
    Yakymovych, Mariya
    Zang, Guangxiang
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Heldin, Carl-Henrik
    CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface2015In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed)
    Abstract [en]

    Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.

  • 34.
    Zang, Guangxiang
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gao, Linlin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landström, Maréne
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model2019In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed)
    Abstract [en]

    Prostate cancer disseminates primarily into the adjacent lymph nodes, which is related to a poor outcome. Atypical protein kinase C ζ (PKCζ) is highly expressed in aggressive prostate cancer and correlates with Gleason score, clinical stage, and poor prognosis. Here, we report the molecular mechanisms of PKCζ in lymphatic metastasis during prostate cancer progression. Using zinc-finger nuclease technology or PKCζ shRNA lentiviral particles, and orthotopic mouse xenografts, we show that PKCζ-knockout or knockdown from aggressive prostate cancer (PC3 and PC3U) cells, decreasesd tumor growth and lymphatic metastasis in vivo. Intriguingly, PKCζ-knockout or knockdown impaired the activation of AKT, ERK, and NF-κB signaling in prostate cancer cells, thereby impairing the expression of lymphangiogenic factors and macrophage recruitment, resulting in aberrant lymphangiogenesis. Moreover, PKCζ regulated the expression of hyaluronan synthase enzymes, which is important for hyaluronan-mediated lymphatic drainage and tumor dissemination. Thus, PKCζ plays a crucial oncogenic role in the lymphatic metastasis of prostate cancer and is predicted to be a novel therapeutic target for prostate cancer.

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