Language：Japanese   Publisher：Biochemical and Biophysical Research Communications  

The canonical Wnt signaling pathway plays a crucial role in embryonic development, tissue homeostasis and cancer progression. The binding of Wnt ligands to their cognate receptors, the Frizzled (Fzd) family of proteins, recruits Dishevelled segment polarity protein (Dvl) to the plasma membrane and induces its phosphorylation via casein kinase 1 (CK1), which leads to the activation of β-catenin. Previous studies showed that Dishevelled-associating protein with a high frequency of leucine residues (Daple) is an important component of the Wnt signaling pathway and essential for Dvl phosphorylation. However, the mechanism by which Daple promotes CK1-mediated phosphorylation of Dvl is not fully understood. In this study, we found that Daple overexpression induced CK1ε-mediated Dvl2 phosphorylation at threonine 224 (Thr224). A Daple mutant (Daple ΔGCV) that lacks a carboxyl-terminal motif to associate with Dvl, retained the ability to interact with CK1ε, but did not induce Dvl phosphorylation, suggesting the importance of the Daple/Dvl/CK1ε trimeric protein complex. We further found that Thr224 phosphorylation of Dvl was required for full activation of β-catenin transcriptional activity. Consistent with this, wild-type Daple promoted β-catenin transcriptional activity, following dissociation of β-catenin and axin. Finally, Wnt3a stimulation increased the membrane localization of Daple and its association with Dvl, and Daple knockdown attenuated Wnt3a-mediated β-catenin transcriptional activity. Collectively, these data suggested a essential role of spatial Daple localization in CK1ε-mediated activation of Dvl in the canonical Wnt signaling pathway.

DOI： 10.1016/j.bbrc.2020.08.066

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PubMed

Language：Japanese   Publisher：iScience  

Despite common consensus about the importance of planar cell polarity (PCP) proteins in tissue orientation, little is known about the mechanisms used by PCP proteins to promote planar polarization of cytoskeletons within individual cells. One PCP protein Fzd6 asymmetrically localizes to the apical cell membrane of multi-ciliated ependymal cells lining the lateral ventricular (LV) wall on the side that contacts cerebrospinal fluid flow. Individual ependymal cells have planar polarized microtubules that connect ciliary basal bodies (BBs) with the cell cortex of the Fzd side to coordinate cilia orientation. Here, we report that cytoplasmic dynein is anchored to the cell cortex of the Fzd side via an adapter protein Daple that regulates microtubule dynamics. Asymmetric localization of cortical dynein generates a pulling force on dynamic microtubules connected to BBs, which in turn orients BBs toward the Fzd side. This is required for coordinated cilia orientation on the LV wall.

DOI： 10.1016/j.isci.2020.101213

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Language：Japanese   Publisher：Cancer Science  

The roles of cancer-associated fibroblasts (CAF) in the progression of various types of cancers are well established. CAF promote cancer progression through pleiotropic mechanisms, including the secretion of soluble factors and extracellular matrix, physical interactions with cancer cells, and the regulation of angiogenesis, immunity and metabolism. Their contribution to therapeutic resistance is also well appreciated. Therefore, CAF have been considered as a therapeutic target in cancer. However, recent studies in autochthonous pancreatic cancer models suggest that specific subset(s) of CAF exhibit cancer-restraining roles, indicating that CAF are functionally and molecularly heterogeneous, which is supported by recent single-cell transcriptome analyses. While cancer-promoting CAF (pCAF) have been extensively studied, the nature and specific marker(s) of cancer-restraining CAF (rCAF) have remained uncharacterized. Interestingly, a recent study provided insight into the nature of rCAF and suggested that they may share molecular properties with pancreatic stellate cells (PSC) and mesenchymal stem/stromal cells (MSC). Complicating this finding is that PSC and MSC have been shown to promote the formation of a tumor-permissive and tumor-promoting environment in xenograft tumor models. However, these cells undergo significant transcriptional and epigenetic changes during ex vivo culture, which confounds the interpretation of experimental results based on the use of cultured cells. In this short review, we describe recent studies and hypotheses on the identity of rCAF and discuss their analogy to fibroblasts that suppress fibrosis in fibrotic diseases. Finally, we discuss how these findings can be exploited to develop novel anticancer therapies in the future.

DOI： 10.1111/cas.14346

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DOI： https://doi.org/10.1158/0008-5472.can-19-0454

DOI： https://doi.org/10.1111/cas.13795