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The protein kinase ...
The protein kinase SIK downregulates the polarity protein Par3
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- Vanlandewijck, Michael, 1982- (author)
- Karolinska Institutet,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Ludwiginstitutet för cancerforskning,Integrated Cardio Metabolic Center, Novum, Karolinska Institute, Huddinge, Sweden
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- Dadras, Mahsa Shahidi (author)
- Uppsala universitet,Ludwiginstitutet för cancerforskning,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Lomnytska, Marta (author)
- Uppsala universitet,Reproduktiv hälsa,Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden
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- Mahzabin, Tanzila (author)
- Uppsala universitet,Ludwiginstitutet för cancerforskning,Science for Life Laboratory, SciLifeLab,School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia
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- Lee Miller, Martin (author)
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark; Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Center, Cambridge, UK
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- Busch, Christer (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Brunak, Søren (author)
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
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- Heldin, Carl-Henrik, 1952- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi,Ludwiginstitutet för cancerforskning
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- Moustakas, Aristidis (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Ludwiginstitutet för cancerforskning
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(creator_code:org_t)
- 2017-12-31
- 2018
- English.
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In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9, s. 5716-5735
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http://www.oncotarge...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
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