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Landström, Maréne
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Publications (10 of 21) Show all publications
Hamidi, A., Song, J., Thakur, N., Itoh, S., Marcusson, A., Bergh, A., . . . Landström, M. (2017). TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α. Science Signaling, 10(486), Article ID eaal4186.
Open this publication in new window or tab >>TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α
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2017 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, article id eaal4186Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-b (TGF-beta) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-beta 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-b 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 p85 alpha and promoted the formation of a complex between the TGF-beta type I receptor (T beta RI) and p85 alpha, which led to the activation of PI3K and AKT. Lys(63)-linked polyubiquitylation of p85 alpha on Lys(513) and Lys(519) in the iSH2 (inter-Src homology 2) domain was required for TGF-beta-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 TbRI. In situ proximity ligation assays revealed that polyubiquitylation of p85a was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-b activates the PI3K-AKT pathway to drive cell migration.

National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-360198 (URN)10.1126/scisignal.aal4186 (DOI)000404615300002 ()28676490 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2012.0090Swedish Cancer Society, CAN 2014/674Swedish Society for Medical Research (SSMF), K2013-66X-15284-04-4 2015-02757
Note

Carl-Henrik Heldin and Maréne Landström contributed equally to this work.

Title in WoS: TGF-beta promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85 alpha.

Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Yakymovych, I., Yakymovych, M., Zang, G., Mu, Y., Bergh, A., Landström, M. & Heldin, C.-H. (2015). CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface. Journal of Cell Biology, 210(2), 319-332
Open this publication in new window or tab >>CIN85 modulates TGF beta signaling by promoting the presentation of TGF beta receptors on the cell surface
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2015 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 210, no 2, p. 319-332Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-260622 (URN)10.1083/jcb.201411025 (DOI)000358457300012 ()
Funder
Knut and Alice Wallenberg Foundation, 2012.0090Swedish Cancer Society, 13 0688
Note

Funding: Ludwig Institute for Cancer Research, Swedish Medical Research Council  K2013-66X-15284-04-4

Available from: 2015-08-24 Created: 2015-08-21 Last updated: 2017-12-04Bibliographically approved
Gudey, S. K., Sundar, R., Mu, Y., Wallenius, A., Zang, G., Bergh, A., . . . Landström, M. (2014). TRAF6 Stimulates the Tumor-Promoting Effects of TGFβ Type I Receptor Through Polyubiquitination and Activation of Presenilin 1. Science signaling, 7(307), ra2
Open this publication in new window or tab >>TRAF6 Stimulates the Tumor-Promoting Effects of TGFβ Type I Receptor Through Polyubiquitination and Activation of Presenilin 1
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2014 (English)In: Science signaling, ISSN 1937-9145, Vol. 7, no 307, p. ra2-Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-β (TGFβ) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGFβ type I receptor (TβRI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-α-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of TβRI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a γ-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGFβ increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the TβRI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved TβRI 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, TβRI-ICD bound to the promoter and increased the transcription of the gene encoding TβRI. The TRAF6- and PS1-induced intramembrane proteolysis of TβRI promoted TGFβ-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the γ-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 TβRI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that γ-secretase inhibitors may be useful for treating aggressive prostate cancer.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-215590 (URN)10.1126/scisignal.2004207 (DOI)000329401100004 ()24399296 (PubMedID)
Available from: 2014-01-15 Created: 2014-01-15 Last updated: 2014-02-12Bibliographically approved
Ekman, M., Mu, Y., Lee, S. Y., Edlund, S., Kozakai, T., Thakur, N., . . . Landström, M. (2012). APC and Smad7 link the TGFβ type I receptors to the microtubule system to promote cell migration. Molecular Biology of the Cell, 23(11), 2109-2121
Open this publication in new window or tab >>APC and Smad7 link the TGFβ type I receptors to the microtubule system to promote cell migration
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2012 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed) Published
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.

Keywords
APC, Smad7, GSK-3beta, p38, TGF-beta, cell migration
National Category
Medical and Health Sciences
Research subject
Cell Research
Identifiers
urn:nbn:se:uu:diva-159146 (URN)10.1091/mbc.E10-12-1000 (DOI)000306286400008 ()
Available from: 2011-09-22 Created: 2011-09-22 Last updated: 2017-12-08Bibliographically 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.

Place, publisher, year, edition, pages
Springer, 2012
Keywords
Non-Smads, Smads, TAK1, TGF beta, TRAF6
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168509 (URN)10.1007/s00441-011-1201-y (DOI)000298800700004 ()
Available from: 2012-02-13 Created: 2012-02-13 Last updated: 2017-12-07Bibliographically approved
Trani, M., Sorrentino, A., Busch, C. & Landström, M. (2009). Pro-apoptotic effect of aurothiomalate in prostate cancer cells. Cell Cycle, 8(2), 306-313
Open this publication in new window or tab >>Pro-apoptotic effect of aurothiomalate in prostate cancer cells
2009 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 8, no 2, p. 306-313Article in journal (Refereed) Published
Abstract [en]

It has been recently demonstrated that small gold compounds could have a potential anti-tumoral activity. Here, we report that aurothiomalate (ATM), a gold compound already used in clinical therapy for the treatment of rheumatoid arthritis, has a pro-apoptotic effect in aggressive prostate cancer (PC3U) cells. In contrast, treatment of human primary epithelial prostate cells (PrEC) with ATM did not cause apoptosis. We demonstrated that ATM is able to disrupt the PKCiota-Par6 complex in PC3U cells and that this disruption leads to the activation of ERK in a dose-dependent manner. Interestingly, we also showed that ERK acts upstream of the activation of caspase 3, leading to apoptosis. ATM treatment also causes activation of p38 and JNK MAP kinases. Moreover we could link ATM treatment to activation of the mitochondrial or so called intrinsic pathway, as we observed release of cytochrome c from mitochondria to cytoplasm, suggesting that the mitochondrial pathway is involved in the pro-apoptotic effect mediated by ATM. Taken together our data suggest that ATM could be a new promising drug for the treatment of advanced prostate cancer.

Keywords
aPKC, apoptosis, aurothiomalate, JNK, p38, Par6, prostate cancer
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-101983 (URN)10.4161/cc.8.2.7596 (DOI)000262622800021 ()19164922 (PubMedID)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
Thakur, N., Sorrentino, A., Heldin, C.-H. & Landström, M. (2009). TGF-beta uses the E3-ligase TRAF6 to turn on the kinase TAK1 to kill prostate cancer cells. Future oncology (London, England), 5(1), 1-3
Open this publication in new window or tab >>TGF-beta uses the E3-ligase TRAF6 to turn on the kinase TAK1 to kill prostate cancer cells
2009 (English)In: Future oncology (London, England), ISSN 1479-6694, Vol. 5, no 1, p. 1-3Article in journal (Refereed) Published
Abstract [en]

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Place, publisher, year, edition, pages
Future Medicine, 2009
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-101981 (URN)10.2217/14796694.5.1.1 (DOI)19243289 (PubMedID)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2009-09-22Bibliographically approved
Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bulow, V., Schuster, N., . . . Landström, M. (2008). The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nature Cell Biology, 10(10), 1199-1207
Open this publication in new window or tab >>The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
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2008 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 10, no 10, p. 1199-1207Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-β signals through its Type II and Type I receptors (TβRII and TβRI) causing phosphorylation of Smad proteins. TGF-β-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-β-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 TβRI. The TβRI–TRAF6 interaction is required for TGF-β-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis. TβRI 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-β-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-β specifically activates TAK1 through interaction of TβRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-101979 (URN)10.1038/ncb1780 (DOI)000259682900014 ()18758450 (PubMedID)
Available from: 2009-04-29 Created: 2009-04-29 Last updated: 2017-12-13Bibliographically approved
Davoodpour, P., Landström, M. & Welsh, M. (2007). Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein. BMC Cancer, 7, 161
Open this publication in new window or tab >>Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein
2007 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 7, p. 161-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Induction of apoptosis is one strategy for treatment of prostate cancer. The Shb adapter protein has been found to regulate apoptosis in various cell types and consequently human prostate cancer 3 (PC3) cells were transfected to obtain cells overexpressing Shb in order to increase our understanding of the mechanisms regulating PC3 cell apoptosis. METHODS: Human prostate cancer cells (PC3) were transfected with control vector or a vector containing the Shb cDNA. Clones overexpressing Shb were studied with respect to apoptosis (Dapi, M30) and c-Abl activation (Western blot for pY-245-Abl). The cells were exposed to the anti-tumor agent 2-methoxyestradiol (2-ME) and the p38 MAPK and c-Abl inhibitors SB203580 and STI-571, respectively, after which cell death was determined. In vivo tumor growth and tumor cell proliferation (Ki-67 staining) or apoptosis (active caspase 3 staining) were also determined in nude mice. RESULTS: PC3 cells overexpressing Shb exhibited increased rates of apoptosis in the presence of the anti-tumor agent 2-ME. The Shb cells displayed increased activity of the pro-apoptotic kinase c-Abl. Pre-treatment with p38 MAPK (SB203580) or c-Abl (STI-571) inhibitors completely blocked 2-ME-induced apoptosis, implicating these two pathways in the response. The PC3-Shb cells displayed reduced tumor growth in vivo, an effect occurring as a consequence of increased apoptosis and reduced DNA synthesis. CONCLUSION: It is concluded that Shb promotes 2-ME-induced PC3 cell apoptosis by increased pro-apoptotic signaling via the c-Abl pathway and that this causes reduced tumor growth in vivo.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-11543 (URN)10.1186/1471-2407-7-161 (DOI)000249382100001 ()17697368 (PubMedID)
Available from: 2008-06-11 Created: 2008-06-11 Last updated: 2017-12-11Bibliographically approved
Roswall, P., Bu, S., Rubin, K., Landström, M. & Heldin, N.-E. (2006). 2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells. Thyroid, 16(2), 143-50
Open this publication in new window or tab >>2-methoxyestradiol induces apoptosis in cultured human anaplastic thyroid carcinoma cells
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2006 (English)In: Thyroid, ISSN 1050-7256, E-ISSN 1557-9077, Vol. 16, no 2, p. 143-50Article in journal (Refereed) Published
Abstract [en]

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.

Keywords
Antineoplastic Agents/pharmacology, Apoptosis, Blotting; Western, Carcinoma/*drug therapy/*metabolism/pathology, Caspases/metabolism, Cell Line; Tumor, DNA Fragmentation, Estradiol/*analogs & derivatives/pharmacology, Flow Cytometry, G1 Phase, Humans, In Situ Nick-End Labeling, MAP Kinase Signaling System, Models; Statistical, Osmosis, RNA; Messenger/metabolism, Research Support; Non-U.S. Gov't, Ribonucleases/metabolism, Thyroid Neoplasms/*drug therapy/*metabolism/pathology, Time Factors, p38 Mitogen-Activated Protein Kinases/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-80918 (URN)16676399 (PubMedID)
Available from: 2006-06-20 Created: 2006-06-20 Last updated: 2017-12-14Bibliographically approved
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