The protein kinase SIK downregulates the polarity protein Par3

Michael Vanlandewijck, Mahsa Shahidi Dadras, Marta Lomnytska, Tanzila Mahzabin, Martin Lee Miller, Christer Busch, Søren Brunak, Carl Henrik Heldin, Aristidis Moustakas

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Abstract

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 saltinducible 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.

Original languageEnglish
Pages (from-to)5716-5735
Number of pages20
JournalOncotarget
Volume9
Issue number5
DOIs
Publication statusPublished - 1 Jan 2018

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Vanlandewijck, M., Dadras, M. S., Lomnytska, M., Mahzabin, T., Miller, M. L., Busch, C., ... Moustakas, A. (2018). The protein kinase SIK downregulates the polarity protein Par3. Oncotarget, 9(5), 5716-5735. https://doi.org/10.18632/oncotarget.23788