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The protein kinase SIK downregulates the polarity protein Par3
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Integrated Cardio Metabolic Center, Novum, Karolinska Institute, Huddinge, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health. Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia.
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2018 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 9, p. 5716-5735Article in journal (Refereed) Published
Abstract [en]

The multifunctional cytokine transforming growth factor β (TGFβ) controls homeostasis and disease during embryonic and adult life. TGFβ alters epithelial cell differentiation by inducing epithelial-mesenchymal transition (EMT), which involves downregulation of several cell-cell junctional constituents. Little is understood about the mechanism of tight junction disassembly by TGFβ. We found that one of the newly identified gene targets of TGFβ, encoding the serine/threonine kinase salt-inducible kinase 1 (SIK), controls tight junction dynamics. We provide bioinformatic and biochemical evidence that SIK can potentially phosphorylate the polarity complex protein Par3, an established regulator of tight junction assembly. SIK associates with Par3, and induces degradation of Par3 that can be prevented by proteasomal and lysosomal inhibition or by mutation of Ser885, a putative phosphorylation site on Par3. Functionally, this mechanism impacts on tight junction downregulation. Furthermore, SIK contributes to the loss of epithelial polarity and examination of advanced and invasive human cancers of diverse origin displayed high levels of SIK expression and a corresponding low expression of Par3 protein. High SIK mRNA expression also correlates with lower chance for survival in various carcinomas. In specific human breast cancer samples, aneuploidy of tumor cells best correlated with cytoplasmic SIK distribution, and SIK expression correlated with TGFβ/Smad signaling activity and low or undetectable expression of Par3. Our model suggests that SIK can act directly on the polarity protein Par3 to regulate tight junction assembly.

Place, publisher, year, edition, pages
2018. Vol. 9, p. 5716-5735
National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-334429DOI: 10.18632/oncotarget.23788PubMedID: 29464029OAI: oai:DiVA.org:uu-334429DiVA, id: diva2:1159617
Note

Michael Vanlandewijck and Mahsa Shahidi Dadras contributed equally to this work.

Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2019-10-11Bibliographically approved
In thesis
1. Regulation of cell polarity and invasion by TGF-β and BMP signaling
Open this publication in new window or tab >>Regulation of cell polarity and invasion by TGF-β and BMP signaling
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways are involved in many physiological processes during embryonic and adult life. TGF-β promotes epithelial to mesenchymal transition (EMT). We identified a gene target of TGF-β signaling, encoding the salt-inducible kinase 1 (SIK1). A potential substrate of this kinase, the polarity protein Par3, is an established regulator of tight junction assembly. SIK1 associates with Par3, can potentially phosphorylate Par3 and leads to its degradation, contributing to tight junction disassembly.

Glioblastoma multiforme (GBM) is a common malignancy in the central nervous system, characterized by high heterogeneity, invasiveness, and resistance to therapy. One of the causes of heterogeneity and therapy-resistance is the existence of glioblastoma stem cells (GSCs). TGF-β signaling promotes self-renewal while BMP signaling induces differentiation of GSCs. Snail is a potent inducer of the EMT in carcinomas. However, in the context of GBM, Snail induces BMP signaling and represses TGF-β signaling through interaction with SMADs, the signaling mediators of TGF-β and BMP. In conclusion, Snail differentially regulates the activity of the opposing BMP and TGF-β pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

Although profound changes in cell polarity is a hallmark of invasive malignancies, little is known about the role of the polarity machinery in tumor suppression. Patient transcriptomic data suggested low Par3 expression, correlating with poor survival of the GBM patients. Par3 silencing decreased the GSC self-renewal capacity and enhanced their invasiveness. Transcriptomic analysis indicates that loss of Par3 leads to downregulation of genes encoding mitochondrial enzymes that generate ATP. These results support a novel role of Par3 in GBM, beyond its contribution to junctional contacts between cells.

Another regulator of TGF-β and BMP signaling is the liver kinase B1 (LKB1). According to GBM patient mRNA analysis, high levels of LKB1 correlate with poor prognosis. Silencing of LKB1 in GSCs impairs invasion and self-renewal capacity due to downregulation of genes involved in these processes. Moreover, loss of LKB1 induces mitochondrial dysfunction, leading to decreased ATP levels. Collectively, this thesis has delivered a group of novel regulatory pathways that control critical aspects of cancer cell polarity, invasion and stemness.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1403
Keywords
Cancer, cancer stem cells, invasion, metastasis, polarity, TGF-β signaling.
National Category
Basic Medicine Cell Biology Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-334409 (URN)978-91-513-0171-6 (ISBN)
Public defence
2018-02-23, B42, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Available from: 2017-12-20 Created: 2017-11-23 Last updated: 2018-03-08

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Vanlandewijck, MichaelDadras, Mahsa ShahidiLomnytska, MartaBusch, ChristerHeldin, Carl-HenrikMoustakas, Aristidis

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Vanlandewijck, MichaelDadras, Mahsa ShahidiLomnytska, MartaBusch, ChristerHeldin, Carl-HenrikMoustakas, Aristidis
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Science for Life Laboratory, SciLifeLabLudwig Institute for Cancer ResearchDepartment of Medical Biochemistry and MicrobiologyReproductive HealthDepartment of Immunology, Genetics and Pathology
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