ARIA/HRG regulates AChR epsilon subunit gene expression at the neuromuscular synapse via activation of phosphatidylinositol 3-kinase and Ras/MAPK pathway

J Cell Biol. 1996 July 2; 134(2): 465–476.

PMCID: PMC2120876

This article has been cited by other articles in PMC.

Abstract

AChR-inducing activity (ARIA)/heregulin, a ligand for erbB receptor tyrosine kinases (RTKs), is likely to be one nerve-supplied signal that induces expression of acetylcholine receptor (AChR) genes at the developing neuromuscular junction. Since some RTKs act through Ras and phosphatidylinositol 3-kinase (PI3K), we investigated the role of these pathways in ARIA signaling. Expression of activated Ras or Raf mimicked ARIA-induction of AChR epsilon subunit genes in muscle cells; whereas dominant negative Ras or Raf blocked the effect of ARIA. ARIA rapidly activated erk1 and erk2 and inhibition of both erks also abolished the effect of ARIA. ARIA stimulated association of PI3K with erbB3, expression of an activated PI3K led to ARIA-independent AChR epsilon subunit expression, and inhibition of PI3K abolished the action of ARIA. Thus, synaptic induction of AChR genes requires activation of both Ras/MAPK and PI3K signal transduction pathways.

Full Text

The Full Text of this article is available as a PDF (3.0M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

Altiok, N; Bessereau, JL; Changeux, JP. ErbB3 and ErbB2/neu mediate the effect of heregulin on acetylcholine receptor gene expression in muscle: differential expression at the endplate. EMBO J. 1995 Sep 1;14(17):4258–4266. [PubMed]
Apel, ED; Merlie, JP. Assembly of the postsynaptic apparatus. Curr Opin Neurobiol. 1995 Feb;5(1):62–67. [PubMed]
Bargmann, CI; Hung, MC; Weinberg, RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. [PubMed]
Ben-Baruch, N; Yarden, Y. Neu differentiation factors: a family of alternatively spliced neuronal and mesenchymal factors. Proc Soc Exp Biol Med. 1994 Jul;206(3):221–227. [PubMed]
Ben-Levy, R; Paterson, HF; Marshall, CJ; Yarden, Y. A single autophosphorylation site confers oncogenicity to the Neu/ErbB-2 receptor and enables coupling to the MAP kinase pathway. EMBO J. 1994 Jul 15;13(14):3302–3311. [PubMed]
Blenis, J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. [PubMed]
Boulton, TG; Cobb, MH. Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. Cell Regul. 1991 May;2(5):357–371. [PubMed]
Bourne, HR. Signal transduction. Team blue sees red. Nature. 1995 Aug 31;376(6543):727–729. [PubMed]
Bowe, MA; Fallon, JR. The role of agrin in synapse formation. Annu Rev Neurosci. 1995;18:443–462. [PubMed]
Bruder, JT; Heidecker, G; Rapp, UR. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev. 1992 Apr;6(4):545–556. [PubMed]
Burgering, BM; Bos, JL. Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci. 1995 Jan;20(1):18–22. [PubMed]
Cantley, LC; Auger, KR; Carpenter, C; Duckworth, B; Graziani, A; Kapeller, R; Soltoff, S. Oncogenes and signal transduction. Cell. 1991 Jan 25;64(2):281–302. [PubMed]
Carraway, KL, 3rd; Cantley, LC. A neu acquaintance for erbB3 and erbB4: a role for receptor heterodimerization in growth signaling. Cell. 1994 Jul 15;78(1):5–8. [PubMed]
Carraway, KL, 3rd; Burden, SJ. Neuregulins and their receptors. Curr Opin Neurobiol. 1995 Oct;5(5):606–612. [PubMed]
Carraway, KL, 3rd; Soltoff, SP; Diamonti, AJ; Cantley, LC. Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erbB3. J Biol Chem. 1995 Mar 31;270(13):7111–7116. [PubMed]
Chahine, KG; Baracchini, E; Goldman, D. Coupling muscle electrical activity to gene expression via a cAMP-dependent second messenger system. J Biol Chem. 1993 Feb 5;268(4):2893–2898. [PubMed]
Chu, GC; Moscoso, LM; Sliwkowski, MX; Merlie, JP. Regulation of the acetylcholine receptor epsilon subunit gene by recombinant ARIA: an in vitro model for transynaptic gene regulation. Neuron. 1995 Feb;14(2):329–339. [PubMed]
Conrad, KE; Oberwetter, JM; Vaillancourt, R; Johnson, GL; Gutierrez-Hartmann, A. Identification of the functional components of the Ras signaling pathway regulating pituitary cell-specific gene expression. Mol Cell Biol. 1994 Mar;14(3):1553–1565. [PubMed]
Corfas, G; Rosen, KM; Aratake, H; Krauss, R; Fischbach, GD. Differential expression of ARIA isoforms in the rat brain. Neuron. 1995 Jan;14(1):103–115. [PubMed]
Culouscou, JM; Plowman, GD; Carlton, GW; Green, JM; Shoyab, M. Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. J Biol Chem. 1993 Sep 5;268(25):18407–18410. [PubMed]
Daum, G; Eisenmann-Tappe, I; Fries, HW; Troppmair, J; Rapp, UR. The ins and outs of Raf kinases. Trends Biochem Sci. 1994 Nov;19(11):474–480. [PubMed]
Dudley, DT; Pang, L; Decker, SJ; Bridges, AJ; Saltiel, AR. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. [PubMed]
Ellis, RW; Defeo, D; Shih, TY; Gonda, MA; Young, HA; Tsuchida, N; Lowy, DR; Scolnick, EM. The p21 src genes of Harvey and Kirsten sarcoma viruses originate from divergent members of a family of normal vertebrate genes. Nature. 1981 Aug 6;292(5823):506–511. [PubMed]
Falls, DL; Rosen, KM; Corfas, G; Lane, WS; Fischbach, GD. ARIA, a protein that stimulates acetylcholine receptor synthesis, is a member of the neu ligand family. Cell. 1993 Mar 12;72(5):801–815. [PubMed]
Fedi, P; Pierce, JH; di Fiore, PP; Kraus, MH. Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members. Mol Cell Biol. 1994 Jan;14(1):492–500. [PubMed]
Feig, LA; Cooper, GM. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol. 1988 Aug;8(8):3235–3243. [PubMed]
Gamett, DC; Greene, T; Wagreich, AR; Kim, HH; Koland, JG; Cerione, RA. Heregulin-stimulated signaling in rat pheochromocytoma cells. Evidence for ErbB3 interactions with Neu/ErbB2 and p85. J Biol Chem. 1995 Aug 11;270(32):19022–19027. [PubMed]
Gundersen, K; Hanley, TA; Merlie, JP. Transgenic embryo yield is increased by a simple, inexpensive micropipet treatment. Biotechniques. 1993 Mar;14(3):412–414. [PubMed]
Hall, ZW; Sanes, JR. Synaptic structure and development: the neuromuscular junction. Cell. 1993 Jan;72 (Suppl):99–121. [PubMed]
Harris, DA; Falls, DL; Dill-Devor, RM; Fischbach, GD. Acetylcholine receptor-inducing factor from chicken brain increases the level of mRNA encoding the receptor alpha subunit. Proc Natl Acad Sci U S A. 1988 Mar;85(6):1983–1987. [PubMed]
Holmes, WE; Sliwkowski, MX; Akita, RW; Henzel, WJ; Lee, J; Park, JW; Yansura, D; Abadi, N; Raab, H; Lewis, GD, et al. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. [PubMed]
Hope, HM; Pike, LJ. Purification and characterization of a polyphosphoinositide phosphatase from rat brain. J Biol Chem. 1994 Sep 23;269(38):23648–23654. [PubMed]
Hu, Q; Klippel, A; Muslin, AJ; Fantl, WJ; Williams, LT. Ras-dependent induction of cellular responses by constitutively active phosphatidylinositol-3 kinase. Science. 1995 Apr 7;268(5207):100–102. [PubMed]
Huang, CF; Lee, YS; Schmidt, MM; Schmidt, J. Rapid inhibition of myogenin-driven acetylcholine receptor subunit gene transcription. EMBO J. 1994 Feb 1;13(3):634–640. [PubMed]
Hunter, T. Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 1995 Jan 27;80(2):225–236. [PubMed]
Jo, SA; Zhu, X; Marchionni, MA; Burden, SJ. Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature. 1995 Jan 12;373(6510):158–161. [PubMed]
Kapeller, R; Cantley, LC. Phosphatidylinositol 3-kinase. Bioessays. 1994 Aug;16(8):565–576. [PubMed]
Klarsfeld, A; Daubas, P; Bourachot, B; Changeux, JP. A 5'-flanking region of the chicken acetylcholine receptor alpha-subunit gene confers tissue specificity and developmental control of expression in transfected cells. Mol Cell Biol. 1987 Feb;7(2):951–955. [PubMed]
Klarsfeld, A; Laufer, R; Fontaine, B; Devillers-Thiéry, A; Dubreuil, C; Changeux, JP. Regulation of muscle AChR alpha subunit gene expression by electrical activity: involvement of protein kinase C and Ca2+. Neuron. 1989 Mar;2(3):1229–1236. [PubMed]
Kraus, MH; Issing, W; Miki, T; Popescu, NC; Aaronson, SA. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9193–9197. [PubMed]
Laufer, R; Changeux, JP. Activity-dependent regulation of gene expression in muscle and neuronal cells. Mol Neurobiol. 1989 3(1-2):1–53.Spring–Summer; [PubMed]
Li, L; Zhou, J; James, G; Heller-Harrison, R; Czech, MP; Olson, EN. FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains. Cell. 1992 Dec 24;71(7):1181–1194. [PubMed]
Marchionni, MA; Goodearl, AD; Chen, MS; Bermingham-McDonogh, O; Kirk, C; Hendricks, M; Danehy, F; Misumi, D; Sudhalter, J; Kobayashi, K, et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature. 1993 Mar 25;362(6418):312–318. [PubMed]
Marte, BM; Graus-Porta, D; Jeschke, M; Fabbro, D; Hynes, NE; Taverna, D. NDF/heregulin activates MAP kinase and p70/p85 S6 kinase during proliferation or differentiation of mammary epithelial cells. Oncogene. 1995 Jan 5;10(1):167–175. [PubMed]
Martinou, JC; Falls, DL; Fischbach, GD; Merlie, JP. Acetylcholine receptor-inducing activity stimulates expression of the epsilon-subunit gene of the muscle acetylcholine receptor. Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7669–7673. [PubMed]
McCormick, F. Activators and effectors of ras p21 proteins. Curr Opin Genet Dev. 1994 Feb;4(1):71–76. [PubMed]
McMahan, UJ; Horton, SE; Werle, MJ; Honig, LS; Kröger, S; Ruegg, MA; Escher, G. Agrin isoforms and their role in synaptogenesis. Curr Opin Cell Biol. 1992 Oct;4(5):869–874. [PubMed]
Merlie, JP; Sanes, JR. Concentration of acetylcholine receptor mRNA in synaptic regions of adult muscle fibres. Nature. 317(6032):66–68. [PubMed]
Miwa, T; Kedes, L. Duplicated CArG box domains have positive and mutually dependent regulatory roles in expression of the human alpha-cardiac actin gene. Mol Cell Biol. 1987 Aug;7(8):2803–2813. [PubMed]
Moscoso, LM; Chu, GC; Gautam, M; Noakes, PG; Merlie, JP; Sanes, JR. Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle. Dev Biol. 1995 Nov;172(1):158–169. [PubMed]
Mulle, C; Benoit, P; Pinset, C; Roa, M; Changeux, JP. Calcitonin gene-related peptide enhances the rate of desensitization of the nicotinic acetylcholine receptor in cultured mouse muscle cells. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5728–5732. [PubMed]
Newberry, EP; Pike, LJ. Cell-cycle-dependent modulation of EGF-receptor-mediated signaling. Biochem Biophys Res Commun. 1995 Mar 8;208(1):253–259. [PubMed]
Pang, L; Sawada, T; Decker, SJ; Saltiel, AR. Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem. 1995 Jun 9;270(23):13585–13588. [PubMed]
Plowman, GD; Culouscou, JM; Whitney, GS; Green, JM; Carlton, GW; Foy, L; Neubauer, MG; Shoyab, M. Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1746–1750. [PubMed]
Plowman, GD; Whitney, GS; Neubauer, MG; Green, JM; McDonald, VL; Todaro, GJ; Shoyab, M. Molecular cloning and expression of an additional epidermal growth factor receptor-related gene. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4905–4909. [PubMed]
Prody, CA; Merlie, JP. A developmental and tissue-specific enhancer in the mouse skeletal muscle acetylcholine receptor alpha-subunit gene regulated by myogenic factors. J Biol Chem. 1991 Nov 25;266(33):22588–22596. [PubMed]
Pronin, AN; Gautam, N. Interaction between G-protein beta and gamma subunit types is selective. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6220–6224. [PubMed]
Robbins, DJ; Zhen, E; Cheng, M; Xu, S; Ebert, D; Cobb, MH. MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. Adv Cancer Res. 1994;63:93–116. [PubMed]
Samuels, ML; Weber, MJ; Bishop, JM; McMahon, M. Conditional transformation of cells and rapid activation of the mitogen-activated protein kinase cascade by an estradiol-dependent human raf-1 protein kinase. Mol Cell Biol. 1993 Oct;13(10):6241–6252. [PubMed]
Sandrock, AW, Jr; Goodearl, AD; Yin, QW; Chang, D; Fischbach, GD. ARIA is concentrated in nerve terminals at neuromuscular junctions and at other synapses. J Neurosci. 1995 Sep;15(9):6124–6136. [PubMed]
Sanes, JR; Schachner, M; Covault, J. Expression of several adhesive macromolecules (N-CAM, L1, J1, NILE, uvomorulin, laminin, fibronectin, and a heparan sulfate proteoglycan) in embryonic, adult, and denervated adult skeletal muscle. J Cell Biol. 1986 Feb;102(2):420–431. [PubMed]
Sanes, JR; Johnson, YR; Kotzbauer, PT; Mudd, J; Hanley, T; Martinou, JC; Merlie, JP. Selective expression of an acetylcholine receptor-lacZ transgene in synaptic nuclei of adult muscle fibers. Development. 1991 Dec;113(4):1181–1191. [PubMed]
Schlessinger, J. SH2/SH3 signaling proteins. Curr Opin Genet Dev. 1994 Feb;4(1):25–30. [PubMed]
Sevetson, BR; Kong, X; Lawrence, JC., Jr Increasing cAMP attenuates activation of mitogen-activated protein kinase. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10305–10309. [PubMed]
Simon, AM; Hoppe, P; Burden, SJ. Spatial restriction of AChR gene expression to subsynaptic nuclei. Development. 1992 Mar;114(3):545–553. [PubMed]
Soltoff, SP; Carraway, KL, 3rd; Prigent, SA; Gullick, WG; Cantley, LC. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994 Jun;14(6):3550–3558. [PubMed]
Sunyer, T; Merlie, JP. Cell type- and differentiation-dependent expression from the mouse acetylcholine receptor epsilon-subunit promoter. J Neurosci Res. 1993 Oct 1;36(2):224–234. [PubMed]
Usdin, TB; Fischbach, GD. Purification and characterization of a polypeptide from chick brain that promotes the accumulation of acetylcholine receptors in chick myotubes. J Cell Biol. 1986 Aug;103(2):493–507. [PubMed]
Valius, M; Kazlauskas, A. Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. Cell. 1993 Apr 23;73(2):321–334. [PubMed]
Vlahos, CJ; Matter, WF; Hui, KY; Brown, RF. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994 Feb 18;269(7):5241–5248. [PubMed]
Wang, J; Auger, KR; Jarvis, L; Shi, Y; Roberts, TM. Direct association of Grb2 with the p85 subunit of phosphatidylinositol 3-kinase. J Biol Chem. 1995 May 26;270(21):12774–12780. [PubMed]
Wasylyk, B; Hahn, SL; Giovane, A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. [PubMed]
Wen, D; Peles, E; Cupples, R; Suggs, SV; Bacus, SS; Luo, Y; Trail, G; Hu, S; Silbiger, SM; Levy, RB, et al. Neu differentiation factor: a transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell. 1992 May 1;69(3):559–572. [PubMed]
Yao, R; Cooper, GM. Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science. 1995 Mar 31;267(5206):2003–2006. [PubMed]
Zhu, X; Lai, C; Thomas, S; Burden, SJ. Neuregulin receptors, erbB3 and erbB4, are localized at neuromuscular synapses. EMBO J. 1995 Dec 1;14(23):5842–5848. [PubMed]