β-Catenin Nuclear Activation
2006; Lippincott Williams & Wilkins; Volume: 99; Issue: 12 Linguagem: Inglês
10.1161/01.res.0000253139.82251.31
ISSN1524-4571
AutoresThierry Couffinhal, Pascale Dufourcq, Cécile Duplàa,
Tópico(s)Hippo pathway signaling and YAP/TAZ
ResumoHomeCirculation ResearchVol. 99, No. 12β-Catenin Nuclear Activation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBβ-Catenin Nuclear ActivationCommon Pathway Between Wnt and Growth Factor Signaling in Vascular Smooth Muscle Cell Proliferation? Thierry Couffinhal, Pascale Dufourcq and Cécile Duplàa Thierry CouffinhalThierry Couffinhal From the Institut National de la Santé et de la Recherche Médicale (T.C., P.D., C.D.), Inserm U441, Pessac, France; Université Victor Segalen Bordeaux 2 (T.C., P.D., C.D.), Bordeaux, France; Department of Cardiology (T.C.), CHU Groupe Sud, Hôpital Haut Lévêque, Pessac, France. , Pascale DufourcqPascale Dufourcq From the Institut National de la Santé et de la Recherche Médicale (T.C., P.D., C.D.), Inserm U441, Pessac, France; Université Victor Segalen Bordeaux 2 (T.C., P.D., C.D.), Bordeaux, France; Department of Cardiology (T.C.), CHU Groupe Sud, Hôpital Haut Lévêque, Pessac, France. and Cécile DuplàaCécile Duplàa From the Institut National de la Santé et de la Recherche Médicale (T.C., P.D., C.D.), Inserm U441, Pessac, France; Université Victor Segalen Bordeaux 2 (T.C., P.D., C.D.), Bordeaux, France; Department of Cardiology (T.C.), CHU Groupe Sud, Hôpital Haut Lévêque, Pessac, France. Originally published8 Dec 2006https://doi.org/10.1161/01.RES.0000253139.82251.31Circulation Research. 2006;99:1287–1289Understanding how smooth muscle cells transition from a steady state to a proliferative state will have an important impact on our understanding of vascular pathology. In the present issue of Circulation Research, Quasnichka et al take an indepth look at the role of the β-catenin/T-cell factor (TCF) signaling pathway in vascular smooth muscle cell (VSMC) proliferation.1 Although β-catenin is the central component in the Wnt canonical pathway, and is regarded as a hallmark of Wnt pathway activation, the present article and other recent reports elucidate new insights into activation of the β-catenin pathway and indicates, that β-catenin activation appears to be intricately orchestrated by both Wnt and growth factor networks.Central Role and Sharp Regulation of β-Catenin at the Molecular and Cellular LevelsAt the plasma membrane, it controls cell-cell adhesion through its binding with cadherin in adherence junctions and also mediates the link between cadherin and the actin cytoskeleton through the molecular switch α-catenin.2,3 In addition, β-catenin acts as a transcriptional activator and regulates transcription of target genes responsible for cell proliferation and differentiation.4 Literature diverges on the interpretation of the interplay between these pathways. It is still unclear if these 2 processes act in concert or independently.5,6The Wnt system is 1 of the well-known potent pathways, which activates nuclear β-catenin. In the absence of Wnt signal, free cytoplasmic β-catenin is phosphorylated by serine/threonine kinases, casein Kinase Iα (CKIα) and GSK3β in a large APC/axin scaffolding complex that targets β-catenin for degradation. In the presence of Wnt signaling, this destruction complex is disrupted, and dissociation of GSK3β prevents phosphorylation of β-catenin. The increase stability of β-catenin following Wnt activation leads to its translocation in the nucleus and induces transcriptional activation of target genes by β-catenin interaction with TCF/LEF (lymphoid enhancer factor) DNA-binding proteins (Figure). Download figureDownload PowerPointThe multiple routes of β-catenin activation. In cells not exposed to a Wnt signal, β-catenin is degraded through interactions with Axin, APC, and the protein kinase GSK3β. Wnt proteins bind to the Frizzled/LRP receptor complex at the cell surface. These receptors transduce a signal to Dishevelled (Dvl) and to Axin. As a consequence, the degradation of β-catenin is inhibited, and this protein accumulates in the cytoplasm and nucleus. β-catenin then interacts with TCF to control transcription of crucial target genes. β -catenin also functions in cell adhesion at the plasma membrane, by linking cadherins to α-catenin. This switch can be regulated by receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (Fer, Fyn, Met, and c-Src), which phosphorylate specific tyrosine residues in β-catenin, which leads to dissociation of the cadherin-catenin complex, and the β-catenin locates to the nucleus. As demonstrated in this article, growth factors (PDGF) can induce β-catenin nuclear activation. PDGF stimulation was also demonstrated to induce p68 phosphorylation which then binds β-catenin leading to the axin-GSK3β dissociation and then to β-catenin nuclear translocation. APC indicates adenoma polyposis coli; GSK3β, glycogen synthase kinase; CKI, casein kinase I α; LRP, lipoprotein receptor-related protein; LEF/TCF, lymphoid enhancer factor/T-cell factorRegulation of β-catenin activity is thought to occur mainly at the level of protein degradation but there is considerable evidence now that its activity depends on its subcellular localization, which is regulated by interaction with distinct partners.7 LEF/TCF8,9 and a complex of B-cell lymphoma 9 (BCL9)10,11 can recruit β-catenin in the nucleus. Conversely, axin as APC complex promotes a nuclear-cytoplasmic shuttling of β-catenin and regulates β-catenin subcellular distribution.12 Gottardi et al proposed that under Wnt stimuli, a monomeric form of β-catenin interacts preferentially with LEF/TCF transcription factor and not with cadherin, while β-catenin-α-catenin dimer would be involved in adhesion complex.13The function of β-catenin is regulated sharply through tyrosine phosphorylation on 2 tyrosine residues 142 and 654 and results in the disruption of cadherin binding. Tyrosine 654 phosphorylation, by c-src for example, is essential for β-catenin/E-cadherin complex stabilization. Interestingly, phosphorylation of β-catenin at tyrosine 142 by distinct tyrosine kinases, such as Met, Fer, or Fyn kinase,14 diminishes β-catenin affinity to α-catenin in the E-cadherin complex but enhances its binding to the transcriptional coactivator BCL9–2.15 This leads, in conjunction with LEF/TCF, to increased transcriptional activities.Growth Factor Induced β-Catenin/TCF Pathway for Vascular Cell ProliferationIn an elegant series of experiments, Quasnichka et al demonstrate how growth factors (PDGF and bFGF), via the activation of β-catenin/TCF signaling, modulate VSMC proliferation through cyclin D1 and p21 modulation.1 The authors have previously shown that VSMC growth factor stimulation leads to N-cadherin shedding, in part by metalloproteinase dependent proteolysis. This is accompanied by translocation of β-catenin to the nucleus, where it associates with the transcription factor LEF-1, playing a direct role in modulating VSMC proliferation.16The authors used a set of original reagents, which warrant description, as they are essential to understanding the study results. To block β-catenin/TCF signaling, they used adenovirus approaches and a cationic lipid delivery of anti-β-catenin antibody. Adenovirus RAd dn-TCF-4 was used to express dominant negative TCF-4. Adenovirus RAd ICAT expressed the β-catenin-interacting protein, ICAT, which inhibits the interaction of β-catenin with TCF, preventing formation of the transactivator complex and thereby negatively regulating β-catenin-TCF–mediated transcription. RAd FL-N-cadherin indirectly inhibited β-catenin/TCF signaling by increasing cell-cell junctions and thereby lowering free cytosolic β-catenin by binding it to the cell membrane.It has been previously shown that cyclin D1 expression is increased and p21 repressed by β-catenin/TCF signaling. Quasnichka et al further demonstrate that PDGF and bFGF activate cyclin D1 promoter, cyclin D1 messenger RNA (mRNA) and protein expression in VSMC and that this activation is partially repressed by inhibiting the β-catenin/TCF pathway or lowering free cytosolic β-catenin. In parallel, the authors report that growth factors do not activate p21 promoter activity or modulate p21 mRNA or protein expression in VSMC. However, inhibiting the β-catenin/TCF pathway lead to an activation of p21 promoter and to an increase in mRNA and protein expression. These results were further corroborated in experiments using human saphenous vein segments.The authors validate their results in cyclin D1 deficient (CD1−/−) and p21 deficient (p21−/−) mouse aortic VSMC. They demonstrate that growth factors induce proliferation of CD1−/− and p21−/− VSMC. In contrast, in wild type VSMC, blocking β–catenin/TCF signaling did not alter this response, confirming that cyclin D1 and p21 are necessary to exert the proliferative effect of β-catenin/TCF signaling induced by growth factors (Figure).Wnt/β-Catenin Signaling in the VasculatureAlthough growth factors are known to coordinate dynamic changes in cell adhesion and proliferation, ongoing studies have now provided strong evidence that the canonical Wnt–β-catenin pathway is of particular importance in adult vascular cell proliferation.17–21Genetic data from mouse studies have emphasized the critical role of some Wnt proteins or their receptors Frizzled (fz) in vascular development. For example, inactivation of Frizzled 5 and Frizzled 4 induced defects in vessels in the yolk sac and placenta22 and in retinal vascular network,23 respectively. Recent analysis of Wnt pathway components in blood vessels revealed that the canonical Wnt–β-catenin pathway is present in vascular cells activated by a vascular lesion or an ischemia event, and this pathway appears to regulate vascular smooth muscle proliferation and apoptosis.24 In vivo, β-catenin stabilization correlates with VSMC proliferation in a rat carotid artery balloon-injury model.20 The same group demonstrated the role for a Wnt coreceptor, the lipoprotein receptor-related protein (LRP-6), in the regulation of VSMC proliferation and survival through the Wnt signaling cascade.19 sFRP-1, a Wnt pathway modulator, was shown to delay the G1 phase and entry into S-phase of EC and VSMC and also modulated the levels of the cyclin D1, E and the associated cyclin-dependent kinases cdk2 and cdk4.18 This effect was in part β-catenin dependent. Others have observed that, after myocardial injury, β-catenin is translocated from the plasma membrane to the cytoplasm of endothelial cells during the phase of neovascularization of the infarct area21 and that sFRP-1 overexpression decreased β-catenin cytosolic accumulation in vascular cells compared with that in control mouse hearts.25Thus, the work of Quasnichka et al elicits important questions for the vascular field. How do Wnt and growth factors signal through β-catenin nuclear activation? Do they regulate through a parallel or common pathway? By which molecular mechanism is the dual function of β-catenin in cell adhesion and gene transcription regulated? A recent clue to another route, parallel to the Wnt pathway, for β-catenin translocation has begun to emerge. Yang et al propose in a model of epithelial-mesenchymal transition, in which PDGF activation induces p68 RNA Helicase phosphorylation, displacing the complex axin-GSK3β from β-catenin, favoring its translocation in the nucleus,6 independently of the Wnt pathway (Figure).The tight regulation of the balance between a quiescent VSMC firmly adherent to the extra cellular matrix or to a neighboring cell and a VSMC that dismantles its junctions, proliferates and migrates is a key point of many vascular diseases, such as atherosclerosis, vascular rejection or restenosis after angioplasty but also neovessel muscularization and maturation in ischemic or in tumor diseases. β-catenin is at the crossroad of growth factor and morphogen paths that sharply control VSMC proliferation. Understanding the interactions between these pathways is an exciting challenge.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Sources of FundingT.C., P.D., and C.D. work was supported by the Inserm, Université de Bordeaux 2, IFR4-FR21, Fondation de France, European Vascular Genomic Network, Agence Nationale de la Recherche, Groupe de Réflexion sur la Recherche Cardiovasculaire, and the Foundation pour la Recherche Médicale.DisclosuresNone.FootnotesCorrespondence to Thierry Couffinhal, MD, PhD, Inserm U 441, Avenue du Haut-Lévêque, 33600 Pessac, France. E-mail [email protected] References 1 Quasnichka H, Slater SC, Beeching CA, Boehm B, Sala-Newby GB, George SJ. Regulation of Smooth Muscle Cell Proliferation by [beta]-catenin/TCF Signaling Involves Modulation of Cyclin D1 and p21 Expression. Circ Res. 2006; 99: 1329–1337.LinkGoogle Scholar2 Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI. 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