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.
Highlights
The transforming growth factor β (TGFβ) pathway is a highly conserved signaling engine [1] that plays major roles in different cellular processes, including proliferation, apoptosis and differentiation [2]
We found that saltinducible kinase 1 (SIK) plays a role in mediating tight junction stability by degrading Par3, a key member of the polarity complex (Figure 2)
We observed that knockdown of endogenous SIK resulted in enhanced stability of the tight junctions (TJ) complex and partial resistance against TGFβ-induced depolarization of the Golgi apparatus and dissolution of the epithelial cilium, while overexpression of SIK led to enhanced degradation of the TJs (Figure 4)
Summary
The transforming growth factor β (TGFβ) pathway is a highly conserved signaling engine [1] that plays major roles in different cellular processes, including proliferation, apoptosis and differentiation [2]. TGFβ shows a prominent role as a tumor suppressor during initial stages of tumorigenesis by preventing cell growth. It functions as an important promoter of tumor spread in later stages of cancer progression by enhancing tumor www.impactjournals.com/oncotarget cell dedifferentiation towards a more invasive phenotype [5]. TGFβ signaling is initiated by binding of the dimeric TGFβ ligand to a heteromeric receptor complex of two type I (TGFβRI) and two type II (TGFβRII) homodimeric subunits [6, 7]. The kinase of TGFβRII is constitutively active and as a consequence, heteromerization leads to phosphorylation and activation of TGFβRI [8] This event leads to phosphorylation of the receptor-regulated Smad and Smad, allowing complex formation with the common mediator Smad. The Smad complexes accumulate in the nucleus where they influence transcription by binding to DNA in cooperation with a plethora of other transcription factors [1, 4, 9]
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