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Stabilization of Я-Catenin by a Wnt-Independent Mechanism

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Stabilization of Я-Catenin by a Wnt-Independent Mechanism Stabilization of ␤-catenin by a Wnt-independent mechanism regulates cardiomyocyte growth Syed Haq*†, Ashour Michael*, Michele Andreucci‡, Kausik Bhattacharya*, Paolo Dotto‡, Brian Walters*, James Woodgett§, Heiko Kilter*, and Thomas Force*† *Molecular Cardiology Research Institute, Tufts–New England Medical Center, and Tufts University School of Medicine, Boston, MA 02111; ‡Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and §University of Toronto, Toronto, Ontario, Canada M5S 1A1 Communicated by Alexander Leaf, Harvard University, Charlestown, MA, February 21, 2003 (received for review September 30, 2002) ␤-Catenin is a transcriptional activator that regulates embryonic phorylation inhibits GSK-3 activity directed toward primed development as part of the Wnt pathway and also plays a role in substrates that have been previously phosphorylated at a site tumorigenesis. The mechanisms leading to Wnt-induced stabiliza- four residues carboxy terminal to the GSK-3 phosphorylation tion of ␤-catenin, which results in its translocation to the nucleus site but does not inhibit kinase activity directed toward unprimed and activation of transcription, have been an area of intense substrates (15, 16). This mechanism is used in growth factor interest. However, it is not clear whether stimuli other than Wnts signaling but is not believed to be important in Wnt signaling and can lead to important stabilization of ␤-catenin and, if so, what has been reported to be insufficient to induce ␤-catenin accu- factors mediate that stabilization and what biologic processes mulation (17, 18). Although these data are compatible with might be regulated. Herein we report that ␤-catenin is stabilized in ␤-catenin being unprimed in situ (19), recent studies indicate that cardiomyocytes after these cells have been exposed to hypertro- ␤-catenin can exist as a primed target for GSK-3, when phos- phic stimuli in culture or in vivo. The mechanism by which ␤-catenin phorylated on Ser-45 by casein kinase 1␣ (20), and raise the is stabilized is distinctly different from that used by Wnt signaling. possibility that, in certain circumstances, Ser-9 phosphorylation Although, as with Wnt signaling, inhibition of glycogen synthase of GSK-3␤ could stabilize ␤-catenin. A second mechanism of kinase-3 remains central to hypertrophic stimulus-induced stabili- inhibition of GSK-3, used by Wnts, involves, in part, complex zation of ␤-catenin, the mechanism by which this occurs involves formation of GSK-3 with GSK-3-binding protein͞Frat1 (21, 22). the recruitment of activated PKB to the ␤-catenin-degradation Complex formation is believed to sequester GSK-3 and primarily complex. PKB stabilizes the complex and phosphorylates glycogen inhibit phosphorylation of unprimed substrates, at least in kinase synthase kinase-3 within the complex, inhibiting its activity di- assays in vitro (12, 15). rected at ␤-catenin. Finally, we demonstrate via adenoviral gene Increases in ␤-catenin levels in the cytosol, together with less transfer that ␤-catenin is both sufficient to induce growth in well defined signals, lead to its translocation to the nucleus, cardiomyocytes in culture and in vivo and necessary for hypertro- where it acts in tandem with T cell factor (Tcf)͞lymphocyte phic stimulus-induced growth. Thus, in these terminally differen- enhancer factor (Lef) family members to induce expression of ␤ tiated cells, -catenin is stabilized by hypertrophic stimuli acting several genes involved in cell cycle reentry, as well as in transfor- via heterotrimeric G protein-coupled receptors. The stabilization mation of postnatal cells (23, 24). In this manuscript, we ask what occurs via a unique Wnt-independent mechanism and results in role, if any, this pathway might be playing in terminally differenti- cellular growth. ated cells that cannot enter the cell cycle and whether the mech- anisms regulating ␤-catenin stability differed in these cells (11). lycogen synthase kinase-3 (GSK-3)-␣ and -␤ function as Ginhibitors of Wnt signaling during the development of the Methods embryonic axis (1). GSK-3 is also a negative regulator of growth Adenoviruses. AdGFP, Ad␤-catenin, and Ad␤-catenin⌬ contain in cardiomyocytes, cells that are terminally differentiated and cytomegalovirus-driven expression cassettes for enhanced GFP can only undergo hypertrophic growth (2–4). Inhibition of and either ␤-galactosidase or vesicular stomatitis virus-tagged GSK-3 is necessary for the hypertrophic response both in vitro ␤-catenin or ␤-catenin⌬ (␤-catenin deleted for the N-terminal and in vivo (2–5), and at least some of the antihypertrophic 134 amino acids, a region that contains the GSK-3 phosphory- effects of active GSK-3 are mediated by regulating activity of the lation sites), respectively, substituted for E1 through homologous nuclear factor of activated T cells (NF-AT) family of transcrip- recombination (24). AdGSK-3␤(S9A), encoding GSK-3␤ with a tion factors (2, 5, 6). However, we found that gene transfer of an Ser-9-to-Ala mutation has been described (2). AdNF-AT⌬, activated NF-AT3 failed to recapitulate the full hypertrophic provided by Jeffery Molkentin (Children’s Hospital Medical response and asked whether additional GSK-3 targets could play Center, Cincinnati), encodes NF-AT3 deleted for the first 317 a role. ␤-Catenin, which plays critical roles in development and amino acids and is constitutively active (6). tumorigenesis (7, 8), is one potential target. The protein exists in the cell in two pools, membrane associated and cytosolic. In Cell Culture. Neonatal rat ventricular myocytes (NRVM). Cardiomyo- the membrane, ␤-catenin links cadherins to the cytoskeleton (9). cytes were prepared from 1- to 2-d-old rats by using standard ␤-Catenin also functions as a transcriptional coactivator (8), the methods (2). source of this being the cytosolic pool, which is negatively S2-Wingless (Wg)-secreting cells. S2 cells expressing Drosophila Wg regulated by GSK-3. GSK-3 phosphorylates the amino-terminal under the control of the metallothionein promoter were as ␤ region of -catenin, targeting it for ubiquitination and degra- described (25). Production of Wg was induced by addition of dation by the proteasome (10, 11). ␤-Catenin is phosphorylated by GSK-3 when part of a complex that includes the scaffolding protein Axin and the adenomatous polyposis coli gene product, Abbreviations: GSK-3, glycogen synthase kinase-3; NF-AT, nuclear factor of activated T cells; APC (12). Inhibition of GSK-3 is therefore essential for the Tcf, T cell factor; Lef, lymphocyte enhancer factor; NRVM, neonatal rat ventricular ␤ myocytes; Wg, Wingless; CSA, cross-sectional area; TAC, thoracic aortic constriction; PE, stabilization and accumulation of -catenin. phenylephrine. GSK-3 activity is inhibited via two primary mechanisms. One, †To whom correspondence should be addressed at: Tufts–New England Medical Center, 750 phosphorylation of an amino-terminal serine residue (Ser-21 for Washington Street, Box 8486, Boston, MA 02111. E-mail: [email protected] or ␣, Ser-9 for ␤; ref. 13), is catalyzed by PKB (14). This phos- [email protected]. 4610–4615 ͉ PNAS ͉ April 15, 2003 ͉ vol. 100 ͉ no. 8 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0835895100 Downloaded by guest on September 30, 2021 CdCl2 to the culture medium to a final concentration of 0.1 mM. Media was collected 6 h later. Although Drosophila in origin, when added to mammalian cells, Wg activates the Wnt pathway (see Fig. 1D). Luciferase Assays. Plasmids: pTOPFlash contains three copies of the Tcf͞Lef binding site upstream of the thymidine kinase minimal promoter and luciferase cDNA. pFOPFlash has three copies of a mutated Tcf͞Lef binding site (Upstate Biotechnol- ogy). NRVMs were transfected by using FuGENE 6 (Roche) with 0.2 ␮g of plasmid per 1 ϫ 105 cells. Luciferase activity was determined by using a commercially available assay system (Promega) and was normalized for transfection efficiency with pcDNA3-␤-galactosidase. [3H]Leucine Incorporation. Cardiomyocytes in 12-well dishes were infected with Ad␤-catenin, Ad␤-catenin⌬, AdNF-AT⌬,or AdGFP for 48 h. For the final 14 h, [3H]leucine (1 ␮Ci per well) was added. [3H]Leucine incorporation was determined as de- scribed (2). Immunoprecipitation and Immunoblotting. Immunoblotting of whole-cell lysates from cardiomyocytes in culture or the intact heart was performed as described (2, 26). Lysates were routinely blotted with antibodies against actin or GAPDH to confirm equivalent loading. All immunoblots shown are representative of at least three. Cytosolic Fractionation. NRVMs were fractionated by hypotonic lysis as described (2), except that the centrifugation was per- formed at 100,000 ϫ g. Immunoblotting with an anticaveolin antibody has confirmed that, with this protocol, there is no contamination of the cytosolic fractions with membrane components. Fig. 1. Hypertrophic stimuli induce ␤-catenin accumulation in vitro and in Immunocytochemistry. NRVMs on coverslips were transduced vivo.(A) NRVMs were treated with PE (100 ␮M), endothelin-1 (100 nM), or, as with viruses or transfected with plasmids, and cells were stained a positive control, with the GSK-3 inhibitor LiCl (10 mM), for the times indicated. Cytosolic fractions were blotted with anti-␤-catenin antibody. An- with antibodies noted in figure legends. Cardiomyocyte area was tiactin blot confirms equivalent protein loading. (B) NRVMs were transfected determined as described (2) by using OPENLAB software from with pTOPFlash or pFOPFlash and 24 h later were
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