The Dishevelled Protein Family

Mlodzik, Marek

doi:10.1016/bs.ctdb.2015.11.027

Cited by 67 publications

(69 citation statements)

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“…S7G,C–F). While Dsh levels are increased in Nek2KD scenarios, Dsh is also mislocalized, and thus the resulting functional effect(s) can be pleiotropic and affect the canonical and PCP branches of Wnt-signaling and possibly other Dsh functions (Mlodzik, 2016). Accordingly, in some of our assays, the effects on Wnt/β–catenin and PCP signaling are not fully separated and wing size reduction and margin pattern defects (both Wg/β–catenin associated defects) are evident.…”

Section: Discussionmentioning

confidence: 99%

“…Dsh levels have to be tightly regulated, because of its several functions (Wallingford and Habas, 2005; Wynshaw-Boris, 2012; Mlodzik, 2016). It has thus been an enigmatic protein family for decades, with new functions still being discovered (Mlodzik, 2016; Wallingford and Habas, 2005; Wynshaw-Boris, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…It has thus been an enigmatic protein family for decades, with new functions still being discovered (Mlodzik, 2016; Wallingford and Habas, 2005; Wynshaw-Boris, 2012). It is the only core PCP factor displaying general lethality when overexpressed (Mlodzik, 2016), which is only in part explained by its role in canonical Wnt-signaling. Dsh behaviour is different from overactivation of canonical Wnt-signaling, as Wnt-pathway components generally cause overgrowth and cell fate defects but not cell lethal outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…Dsh behaviour is different from overactivation of canonical Wnt-signaling, as Wnt-pathway components generally cause overgrowth and cell fate defects but not cell lethal outcomes. Dsh might thus have still undiscovered functions in vivo , which are masked by strong maternal effects in Drosophila and redundancy among the three Dvl genes in mammals (Mlodzik, 2016; Wallingford and Habas, 2005; Wynshaw-Boris, 2012). However, Dsh levels need to be maintained within a specific range, a function that is at least in part provided by the APC/C and Nek2.…”

Section: Discussionmentioning

confidence: 99%

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APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled

Weber

Mlodzik

2017

Developmental Cell

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The Anaphase Promoting Complex/Cyclosome (APC/C) is an E3 ubiquitin ligase, well known for its role in cell cycle progression. However, it has been linked to additional functions, mainly in neuronal contexts, when using the co-activator Cdh1/Fzr. Here, our data indicate a post-mitotic requirement for the APC/CFzr/Cdh1 in epithelial cell patterning and planar cell polarity (PCP) in Drosophila. PCP signalling is critical for development by establishing cellular asymmetries and orientation within the plane of an epithelium, via differential localization of distinct complexes of core PCP factors. Loss of APC/C function leads to reduced Dishevelled (Dsh) levels, a core PCP factor. The effect of APC/C on Dsh is mediated by Nek2 kinase, which can phosphorylate Dsh and is a direct APC/CFzr/Cdh1 substrate. We have thus uncovered a pathway of regulation whereby APC/CFzr/Cdh1 negatively regulates Nek2, which negatively regulates Dsh, to ensure its proper stoichiometric requirement and localization during PCP establishment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled

Weber

Mlodzik

2017

Developmental Cell

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“…Dsh, which acts as a hub mediating both canonical and non-canonical Wg signaling, however, is found at both the apical cell boundary and in the basal side of the cytoplasm (Kaplan and Tolwinski, 2010). Thus, the polarized activity of Dsh must require distinct regulatory mechanisms at different sub-membrane compartments (Mlodzik, 2016). Our results provide the in vivo evidence suggesting that the basolateral polarity determinant Dlg1 may play a dominant role to control the Dsh abundance/activity in canonical Wg signaling.…”

Section: Discussionmentioning

confidence: 99%

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Liu

et al. 2016

eLife

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Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene discs large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC.DOI: http://dx.doi.org/10.7554/eLife.17200.001

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Signalling Underlying Wound Healing

Cook¹,

Hart²,

Zatorski³

et al. 2019

Encyclopedia of Life Sciences

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Wound healing is critical for normal tissue function and the survival of most multicellular organisms. Understanding the biochemical and cellular mechanisms underlying constructive physiological wound healing is crucial for developing therapies to aid in repair and regeneration. Wound healing involves multiple systems including blood, vasculature, somatosensory, immune system and the skin. Following vascular damage, coagulation system activation occurs resulting in clot formation and cell signalling events in both cells of the vasculature (e.g. endothelial cells) as well as circulating cells (e.g. platelets, leukocytes) in order to drive cessation of blood loss. Pain signalling is initiated in part by surrounding inflammatory cues and is used to prevent further damage to the wound. Following these initial responses to the wound, healing/regeneration returns the damaged tissue to a functional state. This occurs by engaging the fibrin network to create a new microenvironment architecture. A broad overview is presented of how the different organ systems are integrated to repair tissue after a wound. Key Concepts Blood coagulation is driven by exposure of the subendothelial receptor tissue factor that drives activation of downstream clotting factors, including activation of the central protease thrombin. Platelet activation is mediated by thrombin cleavage of cell surface protease‐activated receptors, tight receptor‐mediated binding to collagen or activation of the purinergic receptors (i.e. P2Y1, P2Y12). In addition to platelet activation, thrombin catalyses the conversion of fibrinogen into fibrin, the primary structural component of the blood clot. Immune cells like mast cells and macrophages are recruited and activated once a wound occurs, releasing cytokines and histamine. This inflammatory response aids in promoting pain signalling and eventually aids in the wound healing process. In response to the wound and release of inflammatory factors (e.g. cytokines, histamine, bradykinin, NGF and PGE2) sensory neurons become hypersensitive. This hypersensitisation (hyperalgesia) leads to innocuous tactile information to be interpreted as painful by both the peripheral nervous system (PNS) and central nervous system (CNS). Numerous stem cell populations derived from the dermis and hair follicle contribute to wound remodelling. These stem cells differentiate into cell types like myofibroblasts, which either repopulate the site of the wound and/or deposit new extracellular matrix proteins to form a fibrotic scar. A balance between Wnt and TGF‐β signalling guides regenerative and healing processes, respectively. Wnt signalling leads to cell proliferation and the reappearance of hair follicles inducing wounds to heal without a scar. TGF‐β signalling induces reticular dermis stem cells to differentiate into myofibroblasts, which leads to scar tissue.

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The Dishevelled Protein Family

Cited by 67 publications

References 68 publications

APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled

APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Signalling Underlying Wound Healing

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