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  • Vanlandewijck, Michael,1982-Karolinska Institutet,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Ludwiginstitutet för cancerforskning,Integrated Cardio Metabolic Center, Novum, Karolinska Institute, Huddinge, Sweden (author)

The protein kinase SIK downregulates the polarity protein Par3

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • 2017-12-31
  • Impact Journals, LLC,2018
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-334429
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-334429URI
  • https://doi.org/10.18632/oncotarget.23788DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:229464029URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

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

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  • Dadras, Mahsa ShahidiUppsala universitet,Ludwiginstitutet för cancerforskning,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)mahsh538 (author)
  • Lomnytska, MartaUppsala universitet,Reproduktiv hälsa,Department of Oncology and Pathology, Karolinska Biomics Center, Karolinska Institute, Stockholm, Sweden(Swepub:uu)marlo829 (author)
  • Mahzabin, TanzilaUppsala universitet,Ludwiginstitutet för cancerforskning,Science for Life Laboratory, SciLifeLab,School of Anatomy, Physiology and Human Biology, The University of Western Australia, Crawley, WA, Australia (author)
  • Lee Miller, MartinNovo 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 (author)
  • Busch, ChristerUppsala universitet,Institutionen för immunologi, genetik och patologi(Swepub:uu)chrbusch (author)
  • Brunak, SørenNovo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark (author)
  • Heldin, Carl-Henrik,1952-Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi,Ludwiginstitutet för cancerforskning(Swepub:uu)carlheld (author)
  • Moustakas, AristidisUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Ludwiginstitutet för cancerforskning(Swepub:uu)arimo287 (author)
  • Uppsala universitetScience for Life Laboratory, SciLifeLab (creator_code:org_t)

Related titles

  • In:Oncotarget: Impact Journals, LLC9, s. 5716-57351949-2553

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