The protein kinase SIK downregulates the polarity protein Par3.

The protein kinase SIK downregulates the polarity protein Par3. Oncotarget. 2018 Jan 19;9(5):5716-5735 Authors: Vanlandewijck M, Dadras MS, Lomnytska M, Mahzabin T, Lee Miller M, Busch C, Brunak S, Heldin CH, Moustakas A 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 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...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research