The protein kinase SIK downregulates the polarity protein Par3

Oncotarget
Michael VanlandewijckAristidis Moustakas

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. HighSIKmRNA expression also corre...Continue Reading

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Citations

Jan 9, 2020·The New Phytologist·Pierre-François PerroudStefan A Rensing
Aug 14, 2020·Signal Transduction and Targeted Therapy·Zicheng SunJianping Guo
Nov 23, 2018·International Journal of Molecular Sciences·Yutaro Tsubakihara, Aristidis Moustakas
Jun 9, 2021·Oncogene·Farzaneh Atashrazm, Sarah Ellis

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
GTPase
ubiquitination
immunoprecipitation
immunoprecipitations
Co-immunoprecipitation
transfection
fluorescence microscopy
X-ray
biopsies

Software Mentioned

Leica Application Suite
Ensembl
Adobe Photoshop
CS2
QED Camera Plugin
AIDA
Image J
NetPhorest

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