, Volume 7, Issue 6, pp 483–491 | Cite as

Heregulin-induced apoptosis

  • X.-F. Le
  • C. R. Varela
  • R. C. BastJr.


Heregulins (HRGs) are a group of polypeptide factors that are encoded by four different HRG genes that can express multiple isoforms through alternate RNA splicing. A number of HRG isoforms possess both growth stimulatory and growth inhibitory functions that are necessary for their important role in the development and maintenance of the heart, nervous system and epithelial cells in multiple organs including the breast. Growth inhibition by HRG relates to its ability to induce apoptosis, differentiation, and cell cycle G2 arrest. Current studies suggest that HRGs can induce a unique form of apoptosis. In this article, we review recent progress in characterizing and understanding HRG-induced apoptosis. Particular attention has been given to: (1) the activation of caspases-7 and -9; (2) the role of the anti-apoptotic Bcl-2 protein; and (3) the signaling molecules and pathways that regulate HRG-induced apoptosis, including the p38, JNK, mTOR kinase, and PKCα kinase.

apoptosis Bcl-2 breast cancer caspase-7 HER2 heregulin 


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  1. 1.
    Alroy I, Yarden Y The ErbB signaling network in embryogenesis and oncogenesis: Signal diversification through combinatorial ligand-receptor interactions. FEBS Lett 1997; 410: 83–86.PubMedGoogle Scholar
  2. 2.
    Riese DJ 2nd, Stern DF Specificity within the EGF family/ ErbB receptor family signaling network. Bioessays 1998; 20: 41–48.PubMedGoogle Scholar
  3. 3.
    Adlkofer K, Lai C Role of neuregulin in glial cell development. Glia 2000; 29: 104–111.PubMedGoogle Scholar
  4. 4.
    Holmes WE, Sliwkowski MX, Akita RW, et al Identification of heregulin: A specific activator of p185erbB2. Science 1992; 256: 1205–1210.PubMedGoogle Scholar
  5. 5.
    Wen D, Peles E, Cuppies R, et al Neu differentiation factor: A transmembrane glycoprotein containing an EGF domain and an immunoglobulin homology unit. Cell 1992; 69: 559–572.PubMedGoogle Scholar
  6. 6.
    Peles E, Bacus SS, Koski RA, et al Isolation of the neu/HER-2 stimulatory ligand: A 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell 1992; 69: 205–216.PubMedGoogle Scholar
  7. 7.
    Culouscou JM, Plowman GD, Carlton GW, et al Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor. J Biol Chem 1993; 268: 18407–18410.PubMedGoogle Scholar
  8. 8.
    Carraway KL 3rd, Weber JL, Unger MJ, et al Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases. Nature 1997; 387: 512–516.PubMedGoogle Scholar
  9. 9.
    Chang H, Riese DJ 2nd, Gilbert W, et al Ligands for ErbBfamily receptors encoded by a neuregulin-like gene. Nature 1997; 387: 509–512.PubMedGoogle Scholar
  10. 10.
    Zhang D, Sliwkowski MX, Mark M, et al Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4. Proc Natl Acad Sci USA 1997; 94: 9562–9567.PubMedGoogle Scholar
  11. 11.
    Harari D, Tzahar E, Romano J, et al Neuregulin-4: A novel growth factor that acts through the ErbB-4 receptor tyrosine kinase. Oncogene 1999; 18: 2681–2689.PubMedGoogle Scholar
  12. 12.
    Orr-Urtreger A, Trakhtenbrot L, Ben-Levy R, et al Neural expression and chromosomal mapping of Neu differentiation factor to 8p12-p21. Proc Natl Acad Sci USA 1993; 90: 1867–1871.PubMedGoogle Scholar
  13. 13.
    Ring HZ, Chang H, Guilbot A, et al The human neuregulin-2 gene: Cloning, mapping and evaluation as a candidate for the autosomal recessive form of Charcot-Marie-Tooth disease linked to 5q. Hum Genet 1999; 104: 326–332.PubMedGoogle Scholar
  14. 14.
    Gizatullin RZ, Muravenko OV, Al-Amin AN, et al Human NRG3 gene map position 10q22–q23. Chromosome Res 2000; 8: 560.PubMedGoogle Scholar
  15. 15.
    Pinkas-Kramarski R, Shelly M, Guarino BC, et al ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network. Mol Cell Biol 1998; 18: 6090–6101.PubMedGoogle Scholar
  16. 16.
    Jones JT, Akita RW, Sliwkowski MX Binding specificity and affinity of EGF domains for ErbB receptors. FEBS Lett 1999; 447: 227–231.PubMedGoogle Scholar
  17. 17.
    Le XF, Vadlamudi R, McWatters A, et al Differential signaling through p185HER2 with a monoclonal antibody and with heregulin β1 in SKBr3 cells. Cancer Res 2000; 60: 3522–3531.PubMedGoogle Scholar
  18. 18.
    Barnes CJ, Li F, Mandal M, Yang Z, et al Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. Cancer Res 2002; 62: 1251–1255.PubMedGoogle Scholar
  19. 19.
    Meyer D, Birchmeier C Multiple essential functions of neuregulin in development. Nature 1995; 378: 386–390.PubMedGoogle Scholar
  20. 20.
    Gassmann M, Casagranda F, Orioli D, et al Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature 1995; 378: 390–394.PubMedGoogle Scholar
  21. 21.
    Lee KF, Simon H, Chen H, et al Requirement for neuregulin receptor erbB2 in neural and cardiac development. Nature 1995; 378: 394–398.PubMedGoogle Scholar
  22. 22.
    Lewis GD, Lofgren JA, McMurtrey AE, et al Growth regulation of human breast and ovarian tumor cells by heregulin: Evidence for the requirement of ErbB2 as a critical component in mediating heregulin responsiveness. Cancer Res 1996; 56: 1457–1465.PubMedGoogle Scholar
  23. 23.
    Beerli RR, Hynes NE Epidermal growth factor-related peptides activate distinct subsets of ErbB receptors and differ in their biological activities. J Biol Chem 1996; 271: 6071–6076.PubMedGoogle Scholar
  24. 24.
    Aguilar Z, Akita RW, Finn RS, et al Biologic effects of heregulin/ neu differentiation factor on normal and malignant human breast and ovarian epithelial cells. Oncogene 1999; 18: 6050–6062.PubMedGoogle Scholar
  25. 25.
    Weinstein EJ, Leder P The extracellular region of heregulin is sufficient to promote mammary gland proliferation and tumorigenesis but not apoptosis. Cancer Res 2000; 60: 3856–3861.PubMedGoogle Scholar
  26. 26.
    Krane IM, Leder P NDF/heregulin induces persistence of terminal end buds and adenocarcinomas in the mammary glands of transgenic mice. Oncogene 1996; 12: 1781–1788.PubMedGoogle Scholar
  27. 27.
    Bagheri-Yarmand R, Vadlamudi RK, Wang RA, et al Vascular endothelial growth factor upregulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis. J Biol Chem 2000; 275: 39451–39457.PubMedGoogle Scholar
  28. 28.
    Yen L, You XL, Al Moustafa AE, et al Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene 2000; 19: 3460–3469.PubMedGoogle Scholar
  29. 29.
    Xu FJ, Stack S, Boyer C, et al Heregulin and agonistic antip185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): Increased invasiveness may contribute to poor prognosis. Clin Cancer Res 1997; 3: 1629–1634.PubMedGoogle Scholar
  30. 30.
    Tan M, Grijalva R, Yu D Heregulin beta1-activated phosphatidylinositol 3-kinase enhances aggregation of MCF-7 breast cancer cells independent of extracellular signal-regulated kinase. Cancer Res 1999; 59: 1620–1625.PubMedGoogle Scholar
  31. 31.
    Hijazi MM, Thompson EW, Tang C, et al Heregulin regulates the actin cytoskeleton and promotes invasive properties in breast cancer cell lines. Int J Oncol 2000; 17: 629–641.PubMedGoogle Scholar
  32. 32.
    Bacus SS, Huberman E, Chin D, et al A ligand for the erbB-2 oncogene product (gp30) induces differentiation of human breast cancer cells. Cell Growth Differ 1992; 3: 401–411.PubMedGoogle Scholar
  33. 33.
    Daly JM, Jannot CB, Beerli RR, et al Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res 1997; 57: 3804–3811.PubMedGoogle Scholar
  34. 34.
    Le XF, McWatters A, Wiener J, et al Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. Clin Cancer Res 2000; 6: 260–270.PubMedGoogle Scholar
  35. 35.
    Jones FE, Jerry DJ, Guarino BC, et al Heregulin induces in vivo proliferation and differentiation of mammary epithelium into secretory lobuloalveoli. Cell Growth Differ 1996; 7: 1031–1038.PubMedGoogle Scholar
  36. 36.
    Grimm S, Leder P An apoptosis-inducing isoform of neu differentiation factor (NDF) identified using a novel screen for dominant, apoptosis-inducing genes. J Exp Med 1997; 185: 1137–1142.PubMedGoogle Scholar
  37. 37.
    Grimm S, Weinstein EJ, Krane IM, Leder P Neu differentiation factor (NDF): A dominant oncogene, causes apoptosis in vitro and in vivo. J Exp Med 1998; 188: 1535–1539.PubMedGoogle Scholar
  38. 38.
    Weinstein EJ, Grimm S, Leder P The oncogene heregulin induces apoptosis in breast epithelial cells and tumors. Oncogene 1998; 17: 2107–2113.PubMedGoogle Scholar
  39. 39.
    Daly JM, Olayioye MA, Wong AM, et al NDF/heregulininduced cell cycle changes and apoptosis in breast tumour cells: Role of PI3 kinase and p38 MAP kinase pathways. Oncogene 1999; 18: 3440–3451.PubMedGoogle Scholar
  40. 40.
    Guerra-Vladusic FK, Scott G, Weaver V, et al Constitutive expression of Heregulin induces apoptosis in an erbB-2 overexpressing breast cancer cell line SKBr-3. Int J Oncol 1999; 15: 883–892.PubMedGoogle Scholar
  41. 41.
    Le XF, Marcelli M, McWatters A, et al Heregulin-induced apoptosis is mediated by down-regulation of Bcl-2 and activation of caspase-7 and is potentiated by impairment of protein kinase C alpha activity. Oncogene 2001; 20: 8258–8269.PubMedGoogle Scholar
  42. 42.
    Xu FJ, Yu YH, Le XF, et al The outcome of heregulin-induced activation of ovarian cancer cells depends on the relative levels of HER-2 and HER-3 expression. Clin Cancer Res 1999; 5: 3653–3660.PubMedGoogle Scholar
  43. 43.
    Giani C, Casalini P, Pupa SM, et al Increased expression of c-erbB-2 in hormone-dependent breast cancer cells inhibits cell growth and induces differentiation. Oncogene 1998; 17: 425–432.PubMedGoogle Scholar
  44. 44.
    Sepp-Lorenzino L, Eberhard I, Ma Z, et al Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells. Oncogene 1996; 12: 1679–1687.PubMedGoogle Scholar
  45. 45.
    Sartor CI, Zhou H, Kozlowska E, et al HER4 mediates liganddependent antiproliferative and differentiation responses in human breast cancer cells. Mol Cell Biol 2001; 21: 4265–4275.PubMedGoogle Scholar
  46. 46.
    Guerra-Vladusic FK, Vladusic EA, Tsai MS, Lupu R Signaling molecules implicated in heregulin induction of growth arrest and apoptosis. Oncol Rep 2001; 8: 1203–1214.PubMedGoogle Scholar
  47. 47.
    Rouse J, Cohen P, Trigon S, et al A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 1994; 78: 1027–1037.PubMedGoogle Scholar
  48. 48.
    Hagemann C, Blank JL The ups and downs of MEK kinase interactions. Cell Signal 2001; 13: 863–875.PubMedGoogle Scholar
  49. 49.
    Caron E, Hall A Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 1998; 282: 1717–1721.PubMedGoogle Scholar
  50. 50.
    Hauck CR, Meyer TF, Lang F, Gulbins E CD66-mediated phagocytosis of Opa52 Neisseria gonorrhoeae requires a Srclike tyrosine kinase-and Rac1-dependent signalling pathway. EMBO J 1998; 17: 443–454.PubMedGoogle Scholar
  51. 51.
    Kyriakis JM Making the connection: Coupling of stressactivated ERK/MAPK (extracellular-signal-regulated kinase/ mitogen-activated protein kinase) core signalling modules to extracellular stimuli and biological responses. Biochem Soc Symp 1999; 64: 29–48.PubMedGoogle Scholar
  52. 52.
    Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May WS, Jr. Novel role for JNK as a stress-activated Bcl-2 kinase. J Biol Chem 2001; 276: 23681–23688.PubMedGoogle Scholar
  53. 53.
    Bennett BL, Sasaki DT, Murray BW, et al SP600125: An anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA 2001; 98: 13681–13686.PubMedGoogle Scholar
  54. 54.
    Gibson S, Widmann C, Johnson GL Differential involvement of MEK kinase 1 (MEKK1) in the induction of apoptosis in response to microtubule-targeted drugs versus DNA damaging agents. J Biol Chem 1999; 274: 10916–10922.PubMedGoogle Scholar
  55. 55.
    Frisch SM, Vuori K, Kelaita D, Sicks S A role for Jun-Nterminal kinase in anoikis; Suppression by Bcl-2 and crmA. J Biol Chem 1996; 135: 1377–1382.Google Scholar
  56. 56.
    Avruch J, Belham C, Weng Q, Hara K, Yonezawa K. Prog Mol Subcell Biol 2001; 26: 115–154.PubMedGoogle Scholar
  57. 57.
    Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ. Proc Natl Acad Sci USA 2001; 98: 9666–9670.PubMedGoogle Scholar
  58. 58.
    Harris LN, Yang L, Tang C, Yang D, Lupu R. Clin Cancer Res 1998; 4: 1005–1012.PubMedGoogle Scholar
  59. 59.
    Yamamoto K, Ichijo H, Korsmeyer, SJ Bcl-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol Cell Biol 1999; 19: 8469–8478.PubMedGoogle Scholar
  60. 60.
    Thornberry NA, Lazebnik Y Caspases: Enemies within. Science 1998; 281: 1312–1316.Google Scholar
  61. 61.
    Ashkenazi A, Dixit VM Death receptors: Signaling and modulation. Science 1998; 281: 1305–1308.CrossRefPubMedGoogle Scholar
  62. 62.
    Green DR, Reed JC Mitochondria and apoptosis. Science 1998; 281: 1309–1312Google Scholar
  63. 63.
    Nakagawa T, Zhu H, Morishima N, et al Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid. Nature 2000; 403: 98–103.PubMedGoogle Scholar
  64. 64.
    Lee JY, Hannun YA, Obeid LM. J Biol Chem 1996; 271: 13169–13174.CrossRefPubMedGoogle Scholar
  65. 65.
    Whelan RDH, Parker PJ. Oncogene 1998; 16: 1939–1944.PubMedGoogle Scholar
  66. 66.
    Ruvolo PP, Deng X, Carr BK, May WS. J Biol Chem 1998; 273: 25436–25442.PubMedGoogle Scholar
  67. 67.
    Bourbon NA, Yun J, Kester M Ceramide directly activates protein kinase C zeta to regulate a stress-activated protein kinase signaling complex. J Biol Chem 2000; 275: 35617–35623.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • X.-F. Le
    • 1
  • C. R. Varela
    • 1
  • R. C. BastJr.
    • 1
  1. 1.Department of Experimental Therapeutics, Division of Cancer MedicineThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

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