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The Connections of Wnt Pathway Components with Cell Cycle and Centrosome: Side Effects Or a Hidden Logic?

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The Connections of Wnt Pathway Components with Cell Cycle and Centrosome: Side Effects Or a Hidden Logic? Critical Reviews in Biochemistry and Molecular Biology ISSN: 1040-9238 (Print) 1549-7798 (Online) Journal homepage: http://www.tandfonline.com/loi/ibmg20 The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic? Vítězslav Bryja , Igor Červenka & Lukáš Čajánek To cite this article: Vítězslav Bryja , Igor Červenka & Lukáš Čajánek (2017): The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic?, Critical Reviews in Biochemistry and Molecular Biology, DOI: 10.1080/10409238.2017.1350135 To link to this article: http://dx.doi.org/10.1080/10409238.2017.1350135 Published online: 25 Jul 2017. Submit your article to this journal Article views: 72 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ibmg20 Download by: [Masarykova Univerzita v Brne], [Lukas Cajanek] Date: 08 August 2017, At: 01:58 CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY, 2017 https://doi.org/10.1080/10409238.2017.1350135 REVIEW ARTICLE The connections of Wnt pathway components with cell cycle and centrosome: side effects or a hidden logic? Vıtezslav Bryjaa , Igor Cervenka b and Lukas Caj anekc aDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; bMolecular and Cellular Exercise Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; cDepartment of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic ABSTRACT ARTICLE HISTORY Wnt signaling cascade has developed together with multicellularity to orchestrate the develop- Received 10 April 2017 ment and homeostasis of complex structures. Wnt pathway components – such as b-catenin, Revised 29 June 2017 Dishevelled (DVL), Lrp6, and Axin– are often dedicated proteins that emerged in evolution Accepted 29 June 2017 together with the Wnt signaling cascade and are believed to function primarily in the Wnt cas- cade. It is interesting to see that in recent literature many of these proteins are connected with KEYWORDS – cellular functions that are more ancient and not limited to multicellular organisms such as cell Wnt; centrosome; cilium; cycle regulation, centrosome biology, or cell division. In this review, we summarize the recent lit- cell cycle; crosstalk; planar erature describing this crosstalk. Specifically, we attempt to find the answers to the following cell polarity questions: Is the response to Wnt ligands regulated by the cell cycle? Is the centrosome and/or cil- ium required to activate the Wnt pathway? How do Wnt pathway components regulate the cen- trosomal cycle and cilia formation and function? We critically review the evidence that describes how these connections are regulated and how they help to integrate cell-to-cell communication with the cell and the centrosomal cycle in order to achieve a fine-tuned, physiological response. Wnt signaling pathways influences cell fate, proliferation and self-renewal of stem, and progenitor cells throughout the lifespan of Wnt signaling pathway is one of the key signaling cas- metazoa (Korinek et al. 1998, ten Berge et al. 2011). cades, essential for both correct embryo development It revolves around the transcriptional co-activator and tissue homeostasis in adulthood. Research in Wnt b signaling pathways started around 1980, when two -catenin, which is present in the cell in two distinct groups independently reported new morphogenetic pools. It maintains the connection to actin cytoskeleton determinants in Drosophila and mouse (Nusslein- as a component of cadherin junctions and its soluble Volhard and Wieschaus 1980, Nusse and Varmus 1982), cytoplasmic pool serves as a signaling mediator. b respectively. Since then, Wnt signaling has been found Cytoplasmic concentration of -catenin in the cell is to affect a myriad of aspects of cell behavior. kept low by multiprotein complex consisting of Axin, The Wnt signaling pathway is activated by Wnt adenomatous polyposis coli (APC) and glycogen b b ligands – secreted morphogens and drivers of embryo- synthase kinase-3 (GSK-3 ). Without a Wnt signal, genesis that exert their influence over medium to long this destruction complex continually phosphorylates b Downloaded by [Masarykova Univerzita v Brne], [Lukas Cajanek] at 01:58 08 August 2017 range distances. Nineteen homologs are present in the -catenin and targets it for degradation using the ubi- human genome and they are well conserved through- quitin proteasome pathway. For a scheme of the Wnt/ out the animal kingdom. Wnt proteins can activate sev- b-catenin pathway see Figure 1. eral distinct pathways that are shortly introduced The pathway activation’s beginning conforms to below. our view of standard signal transduction. Wnt protein binds the Frizzled receptor (Fz or Fzd) and low-dens- ity-lipoprotein receptor-related proteins 5 and 6 (Lrp5/ Wnt/b-catenin pathway 6) co-receptor forming a ternary complex. Cytoplasmic First discovered and best described, the Wnt/b-catenin portion of this complex is phosphorylated, which pathway, also referred to as the canonical pathway, prompts recruitment of Wnt cascade mediators. CONTACT Vıtezslav Bryja [email protected] Department of Experimental Biology, Faculty of Science, Masaryk University, Brno 61137, Czech Republic ß 2017 Informa UK Limited, trading as Taylor & Francis Group 2 V. BRYJA ET AL. Figure 1. Current view of Wnt/b-catenin signaling in OFF and ON state. During OFF state destruction complex consisting of Axin, APC, and GSK-3b phosphorylates b-catenin and marks it for subsequent degradation via ubiquitin proteasome pathway. At the same time, transcription factors from the TCF/LEF family remain bound to repressors, such as Groucho, blocking the transcription of Wnt target genes. Cascade is activated after binding of Wnt ligand to Frizzled (Fzd) receptor. Subsequently, both DVL and Lrp6 associate to Fzd. Intracellular residues of Lrp6 are phosphorylated and become a site of attachment for scaffold protein Axin, which can no longer serve as assembly site for destruction complex, which is thus desintegrated. It should be noted that phos- phorylated Lrp6, DVL and Axin together with other proteins form a structures dubbed signalosomes that “attract” each other and amplify the Wnt signal. As a result, b-catenin is no longer degraded, and accumulates in the cytoplasm. After reaching a certain threshold, it is translocated to nucleus where it binds to TCF/LEF family of transcription factors, replaces resident repressors thereby co-activating transcription of its target genes. (see color version of this figure at www.tandfonline.com/ibmg) Downloaded by [Masarykova Univerzita v Brne], [Lukas Cajanek] at 01:58 08 August 2017 Dishevelled (DVL) protein binds to Fzd and initiates Cyclin D1, and many others (He et al. 1998, Tetsu and the phosphorylation of cytoplasmic tail of Lrp5/6 McCormick 1999). receptor, which then binds Axin. This renders the destruction complex inactive and stops the constant Receptor complex – Frizzled and LRP5/6. Canonical downregulation of b-catenin, which starts to accumu- Wnts require two receptor sets to propel the signal late in the cytoplasm. Upon reaching a certain thresh- downstream. Frizzled are seven-pass transmembrane b old, -catenin is translocated into the nucleus, where domain receptors belonging to class F of G-protein it couples with transcription factors from the T-cell- coupled receptors (GPCR) (Schulte and Bryja 2007). Due specific transcription factor/Lymphoid enhancer-bind- to the fact that humans encode 10 Fzd receptors and ing factor (TCF/LEF) family. The final outcome of the 19 Wnts, their interaction, affinity, specificity, and signal cascade is the upregulation of genes connected involvement in distinct cascades has been problematic to cell fate and cell proliferation, such as c-Myc, or to elucidate. CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY 3 Lrp5/6 and Drosophila homolog arrow are single- Cytoplasmic events and activation of transcription. span transmembrane proteins that play a vital role The clear sequence of events happening directly below as co-receptors in Wnt/b-catenin signaling. The the membrane after the Wnt initiation signal arrives has intracellular part of Lrp5/6 contains highly conserved not yet been characterized; nevertheless, many facts are PPPS/TPxS/T motif reiterated five times (Tamai et al. known. Lrp5/6 and Fzd are brought into close proxim- 2004) whose phosphorylation is required to activate ity, their association alone is sufficient for Wnt signal ini- downstream signaling as described in detail below. tiation. Fzd function is linked to DVL and DVL is required for Lrp6 phosphorylation. DVL and Axin con- Dishevelled. DVL is a key regulator of Wnt signaling tain homologous DIX domain which confers ability to connecting the receptor complex and downstream form weak homo- or hetero-typic interactions leading effectors. It also stands at the branching point between to aggregation (Bienz 2014). DVL homo-oligomerization Wnt/b-catenin and alternative pathways. Three DVL iso- promotes Fzd-Lrp6 cluster creation and also recruits forms (DVL1, DVL2, and DVL3) are present in mammals Axin to the membrane, facilitating Lrp6 phosphorylation and they have partially specific, partially overlapping by GSK-3b and CK1c. It creates a positive feedback loop functions. Even though many functions of DVL and its and amplifies the signal
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