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Review Transcription Under the Control of Nuclear Arm/B-Catenin View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Current Biology 16, R378–R385, May 23, 2006 ª2006 Elsevier Ltd All rights reserved DOI 10.1016/j.cub.2006.04.019 Transcription under the Control Review of Nuclear Arm/b-Catenin Reto Sta¨ deli1, Raymond Hoffmans1, and Konrad Basler* via a-catenin [5]. Second, Arm/b-catenin acts as a nuclear regulator of Wg/Wnt dependent gene ex- pression and provides transcriptional activator func- The Wingless/Wnt pathway controls cell fates during tions to TCFs. The Arm/b-catenin protein consists of animal development and regulates tissue homeosta- a central region that is made up of 12 imperfect arma- sis as well as stem cell number and differentiation dillo repeats (R1-12) flanked by an amino- and a in epithelia. Deregulation of Wnt signaling has been carboxy-terminal tail [6]. There are mutant forms of associated with cancer in humans. In the nucleus, Arm that interfere with the adhesion function, but not the Wingless/Wnt signal is transmitted via the key ef- with its role in Wg/Wnt signaling, and vice versa, indi- fector protein Armadillo/b-catenin. The recent iden- cating that these two functions of Arm are indepen- tification and functional analysis of novel Armadillo/ dent and separable [7,8]. Interestingly, the nematode b-catenin interaction partners provide new and ex- Caenorhabditis elegans has three different b-catenin citing insights into the highly complex mechanism proteins which are dedicated either to adhesion of Wingless/Wnt target gene activation. (HMP-2) or to Wnt signaling (WRM-1 and BAR-1) [9]. In the absence of a Wg/Wnt signal, cytosolic Arm/ Signaling molecules of the Wingless (Wg)/Wnt family b-catenin is constantly phosphorylated by the action are secreted glycoproteins that control a diverse array of a so-called ‘degradation complex’ consisting of the of processes in embryos and adult animals. The Wnt Adenomatous polyposis coli (APC) protein, Axin, and cascade has been implicated in the postembryonic the kinases Casein kinase I (CKI) and Shaggy/Zeste regulation of stem cell number and differentiation of white-3/Glycogen synthase kinase-3b (GSK-3b). Phos- several adult stem cell systems [1,2]. Moreover, the phorylated Arm/b-catenin is rapidly degraded via the pathway has been causally linked to various diseases, ubiquitin/proteasome pathway [10]. Interaction of the most notably to cancer [3,4]. In the absence of the Wg/Wnt ligand with its receptors Frizzled and Arrow/ Wg/Wnt signal, DNA-bound transcription factors of LDL-receptor-related protein (LRP) blocks the degra- the T-cell factor (TCF) family of HMG-box proteins bind dation complex thus leading to stabilization of Arm/ the transcriptional repressors Groucho (Gro)/TLE and b-catenin. As a consequence, Arm/b-catenin protein Carboxy-terminal binding protein (CtBP). Upon activa- accumulates in the cytoplasm and can enter the nu- tion of the pathway, the key transducing component cleus, where it acts as a co-activator of TCFs [11–16] Armadillo (Arm)/b-catenin becomes stabilized, enters (Figure 1). Artificially preventing Arm from entering the the nucleus and heterodimerizes with TCFs to activate nucleus blocks Wnt signaling [17], while forcing it into the expression of Wg/Wnt target genes. This co-acti- the nucleus can activate target genes [18–20]. There- vator function of Arm/b-catenin depends mainly on two fore, the signaling activity of Arm/b-catenin is largely domains or ‘arms’: An amino-terminal activating arm controlled by the size of its nuclear pool, which de- (NTAA) recruits Legless (Lgs)/B-cell lymphoma 9 pends on the cytoplasmic levels of b-catenin as well (BCL9) and Pygopus (Pygo), while a carboxy-terminal as on the import into and export out of the nucleus. activating arm (CTAA) binds to TATA-binding protein (TBP), Brahma/Brahma-related gene-1 (Brg-1), CREB- Nuclear Import and Export of Arm/b-catenin binding protein (CBP)/p300, Mediator subunit 12 The business of Arm/b-catenin’s import and export is (MED12), and Hyrax/Parafibromin. Despite its thera- rather nebulous and somewhat controversial (Figure 2). peutic relevance, the mechanisms by which Arm/ b-catenin appears to be imported into the nucleus in b-catenin employs these co-factors to control the tran- a NLS- and importin/karyopherin-independent manner scription of target genes are only poorly understood. by directly interacting with nuclear pore components Here, we review past and recent findings that relate [21,22]. Addition of cytosol inhibits nuclear import of to this problem and discuss how they can be inte- b-catenin [21,22], indicative of the presence of cyto- grated into a more complete picture of Wg/Wnt target solic retention factors. Indeed, it was shown that gene activation. Axin could act as such a retention factor in Drosophila [23]. By contrast, Pangolin (Pan), the Drosophila TCF The Dual Role of Arm/b-catenin homologue, can function to keep Arm in the nucleus Arm/b-catenin fulfills two main functions in the cell: [23]. However, a mutant form of Arm, that is defective First, it acts as a component of the cadherin-based in binding Pan, still localizes to the nucleus [7,15].It cell adhesion system. It binds the transmembrane pro- has also been proposed that Lgs in cooperation with tein E-cadherin and regulates actin filament assembly Pygo serves as a nuclear anchor for Arm [20]. How- ever, Arm still localizes to the nucleus in clones of cells that are double-mutant for both axin and pygo, sug- 1 These authors contributed equally. gesting that Pygo acts downstream of Arm nuclear Institut fu¨ r Molekularbiologie, Universita¨ tZu¨ rich, localization [24,25]. These findings show the difficulty Winterthurerstrasse 190, CH-8057 Zu¨ rich, Switzerland. in designing experiments to clearly separate nuclear *E-mail: [email protected] import from retention of Arm/b-catenin. While the Current Biology R379 Figure 1. Simplified overview of the Wg/ Wnt signaling pathway. Wg Arrow In the absence of the Wnt signal (‘OFF’ Arrow Frizzled Frizzled state, left cell), Armadillo (Arm)/b-catenin Dvl Axin protein levels are downregulated by CKI GSK-3β Dvl a complex containing Adenomatous poly- Arm α E-cad Arm posis coli (APC) protein, Axin, Casein Arm APC GSK-3β E-cad α kinase I (CKI), and Glycogen synthase ki- Arm Axin Arm nase-3b (GSK-3b). In addition, the co- CKI α E-cad Arm α Arm repressors Groucho (Gro)/TLE and Car- APC Arm P E-cad Arm boxy-terminal binding protein (CtBP) are Arm bound to T-cell factor (TCF). The cell to the right represents the ‘ON’ state of the pathway. The Wg/Wnt ligand binds Friz- A zled and its co-receptor Arrow/LDL- Pygo r receptor-related protein (LRP). Axin is m Lgs CTAA-BPs Gro bound by Dishevelled (Dvl) and Arrow, CtBP X Arm Ubiquitin TCF TCF thereby disrupting the ‘degradation com- mediated plex’. Arm/b-catenin accumulates in the proteolysis cytoplasm, enters the nucleus and dis- places Gro from TCF. For transcription of b OFF ON target genes Arm/ -catenin interacts Current Biology with Legless (Lgs), which binds Pygopus (Pygo), and with carboxy-terminal activat- ing arm binding proteins (CTAA-BPs), such as TATA-binding protein (TBP), Brahma/Brahma-related gene-1 (Brg-1), CREB-binding protein (CBP)/p300, MED12, and Hyrax/Parafibromin. As part of adherens junctions, Arm/b-catenin binds the transmembrane protein E-cadherin (E-cad) and the cytoplasmic protein a-catenin (a). Negatively acting components of the pathway are colored in red with white letters, while positive components are shown in green with black letters. region comprising R10-C seems to be necessary and in APC [36,37]. Truncated APC can no longer fulfill its sufficient for the nuclear import [26], different regions function in Arm/b-catenin degradation. As a conse- of Arm/b-catenin that interact with binding partners quence, Arm/b-catenin accumulates and enters the such as the above mentioned Pan and Lgs (together nucleus where it activates target genes implicated in with Pygo) could serve as anchor points contributing cell proliferation (e.g. c-Myc and gastrin [38,39]), inhi- to nuclear retention of Arm/b-catenin. bition of apoptosis (e.g. survivin [40]), and tumor pro- To further complicate matters, Arm also has an in- gression (e.g. Laminin g2 [41])(Figure 3). How these trinsic nuclear export activity [21,22,27], which has target genes exert their harmful effect in the various been shown to overlap with its ‘import region’ [26]. steps towards tumorigenesis is currently not well un- Moreover, Axin and APC may facilitate nuclear export derstood. However, especially the Arm/b-catenin tar- of Arm [28–31]. However, a recent paper that investi- gets implicated in cell proliferation would fit into the gated the nucleo-cytoplasmic shuttling of b-catenin view of cancer as a ‘stem cell disease’. and its relation to TCF4, BCL9, APC, and Axin [32] demonstrated that these proteins do not accelerate Initial Steps of Target Gene Activation by Nuclear the import/export rate of b-catenin. Rather, they influ- Arm/b-catenin ence the subcellular localization of b-catenin by retain- How are nuclear Arm/b-catenin targets activated? In ing it in the compartment in which they are localized. In the absence of Arm/b-catenin in the nucleus, Pan/ summary, the intracellular localization of Arm/b-cate- TCF is bound to Gro/TLE [42,43] and CtBP [44–47]. nin represents a dynamic equilibrium of its intrinsic nu- Gro/TLE family proteins are general long-range tran- clear import and export activities as well as the avail- scriptional co-repressors, which have been shown to ability and affinity of its binding partners.
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