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Mu, Yabing
Publications (8 of 8) Show all publications
Zang, G., Mu, Y., Gao, L., Bergh, A. & Landström, M. (2019). PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model. Oncogene, 38(22), 4215-4231
Open this publication in new window or tab >>PKC sigma facilitates lymphatic metastatic spread of prostate cancer cells in a mice xenograft model
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2019 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 38, no 22, p. 4215-4231Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-160292 (URN)10.1038/s41388-019-0722-9 (DOI)000469339100002 ()30705401 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceSwedish Research CouncilSwedish Cancer Society, CAN 2017/544Swedish Cancer Society, 2016/387Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Song, J., Mu, Y., Li, C., Bergh, A., Miaczynska, M., Heldin, C.-H. & Landström, M. (2016). APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain. OncoTarget, 7(1), 279-292
Open this publication in new window or tab >>APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, p. 279-292Article in journal (Refereed) Published
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.

Keywords
APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-117841 (URN)10.18632/oncotarget.6346 (DOI)000369950300023 ()26583432 (PubMedID)
Available from: 2016-03-30 Created: 2016-03-04 Last updated: 2019-05-10Bibliographically 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
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-107163 (URN)10.1083/jcb.201411025 (DOI)000358457300012 ()26169354 (PubMedID)
Available from: 2015-09-02 Created: 2015-08-19 Last updated: 2018-06-07Bibliographically approved
Mu, Y., Zang, G., Engstrom, U., Busch, C. & Landstrom, M. (2015). TGF beta-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells. British Journal of Cancer, 112(7), 1223-1231
Open this publication in new window or tab >>TGF beta-induced phosphorylation of Par6 promotes migration and invasion in prostate cancer cells
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2015 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 7, p. 1223-1231Article in journal (Refereed) Published
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.

Keywords
Invasion, migration, Par6, prostate cancer, TGFβ
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-103553 (URN)10.1038/bjc.2015.71 (DOI)000352145300010 ()25756394 (PubMedID)
Available from: 2015-05-25 Created: 2015-05-21 Last updated: 2018-06-07Bibliographically 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
Ekman, M., Mu, Y., Lee, S. Y., Edlund, S., Kozakai, T., Thakur, N., . . . Landström, M. (2012). APC and Smad7 link TGF beta 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 TGF beta 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.

Place, publisher, year, edition, pages
American Society of Cell Biology, USA, 2012
Keywords
ADENOMATOUS POLYPOSIS-COLI, GROWTH-FACTOR-BETA, PROSTATIC-CARCINOMA CELLS, E-CADHERIN, PROTEIN, CATENIN, APOPTOSIS, KINASE, CANCER, ACTIVATION
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-57614 (URN)10.1091/mbc.E10-12-1000 (DOI)000306286400008 ()
Available from: 2012-08-08 Created: 2012-08-08 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., Song, J., Zang, G., Gao, L., Gahman, T. & Landström, M.TGFβ-induced activation of PKCζ confers invasive prostate cancer growth.
Open this publication in new window or tab >>TGFβ-induced activation of PKCζ confers invasive prostate cancer growth
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(English)Manuscript (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.

Keywords
TRAF6, PKCζ, TGFβ
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-127692 (URN)
Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2018-06-09
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