The protein kinase SIK downregulates the polarity protein Par3

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 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.

The Selective SIK2 Inhibitor ARN-3236 Produces Strong Antidepressant-Like Efficacy in Mice via the Hippocampal CRTC1-CREB-BDNF Pathway

“…However, the neurobiology of depression is very complex, involving not only BDNF but also a lot of other members regulated by CREB, such as mammalian target of rapamycin, vascular endothelial growth factor and peroxisome proliferator-activated receptor alpha ( Clark-Raymond and Halaris, 2013 ; Abelaira et al, 2014 ; Song et al, 2018 ). SIK has also been demonstrated to modulate several other factors than CRTC, including polarity protein Par3, the Hippo signaling pathway and cytoplasmic histone deacetylase 4 ( Wehr et al, 2013 ; Abend et al, 2017 ; Vanlandewijck et al, 2017 ). Therefore, for the pharmacological targets of ARN-3236, currently we could not yet exclude out these proteins mentioned above besides the CRTC1-CREB-BDNF pathway, and more shRNAs will be adopted in the future.…”

Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

“…TGFβ/Smad and MAP-kinase signaling transcriptionally induce expression of the salt-inducible kinase 1 (SIK1), a member of the AMP-regulated protein kinases; SIK1 associates with Smad7 and recruits Smurf2 to the TGFβ type I receptor, promoting its ubiquitination and lysosomal degradation [ 45 , 46 ]. Simultaneously, SIK1 associates with Par3 and promotes its phosphorylation and proteasomal degradation, thus facilitating the TGFβ-induced EMT [ 47 ]. These examples of Par3 and Par6 negative regulation by TGFβ signaling during EMT ( Figure 2 ), suggest that in epithelial cells, tight junction disassembly is coupled to TGFβ receptor internalization and downregulation.…”

DEK1 displays a strong subcellular polarity during Physcomitrella patens 3D growth

“…Such cell polarity maintenance through modulation of protein degradation is a phenomenon observed in other eukaryotic organisms (Bórquez & González‐Billault, ). For example, in zebrafish the protein Retinitis Pigmentosa GTPase Regulator‐Interacting Protein 1‐like prevents dishevelled degradation and maintains planar polarity (Mahuzier et al , ) and in mammalian epithelial cells, the serine/threonine kinase salt induciblekinase 1‐mediated targeting of the polarity determinant like‐polarity complex protein 3 leads to protein degradation and cell polarity loss (Vanlandewijck et al , ).…”