Interaction of the PA2G4 (EBP1) protein with ErbB-3 and regulation of this binding by heregulin (original) (raw)

Abstract

The processes by which ErbB-3, an inactive tyrosine kinase, exerts its biological effects are poorly understood. Using the yeast two-hybrid system, we have isolated an ErbB-3 binding protein (Ebp1) that interacts with the juxtamembrane domain of ErbB-3. This protein is identical to that predicted to be encoded for by the human PA2G4 gene. Ebp1 is the human homologue of a previously identified cell cycle-regulated mouse protein p38-2G4. Two transcripts of ebp1 mRNA (1.7 and 2.2 kb) were detected in several normal human organs. The interaction of Ebp1 with ErbB-3 was examined in vitro and in vivo. The first 15 amino acids of the juxtamembrane domain of ErbB-3 were essential for Ebp1 binding in vitro. Treatment of AU565 cells with the ErbB-3 ligand heregulin resulted in dissociation of Ebp1 from ErbB-3. Ebp1 translocated from the cytoplasm into the nucleus following heregulin stimulation. These findings suggest that Ebp1 may be a downstream member of an ErbB-3-regulated signal transduction pathway. © 2000 Cancer Research Campaign

Keywords: ErbB-3, ErbB-2, heregulin, breast cancer

Full Text

The Full Text of this article is available as a PDF (161.8 KB).

Selected References

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

  1. Bacus S. S., Gudkov A. V., Zelnick C. R., Chin D., Stern R., Stancovski I., Peles E., Ben-Baruch N., Farbstein H., Lupu R. Neu differentiation factor (heregulin) induces expression of intercellular adhesion molecule 1: implications for mammary tumors. Cancer Res. 1993 Nov 1;53(21):5251–5261. [PubMed] [Google Scholar]
  2. Bargmann C. I., Hung M. C., Weinberg R. A. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature. 1986 Jan 16;319(6050):226–230. doi: 10.1038/319226a0. [DOI] [PubMed] [Google Scholar]
  3. Carraway K. L., 3rd, Sliwkowski M. X., Akita R., Platko J. V., Guy P. M., Nuijens A., Diamonti A. J., Vandlen R. L., Cantley L. C., Cerione R. A. The erbB3 gene product is a receptor for heregulin. J Biol Chem. 1994 May 13;269(19):14303–14306. [PubMed] [Google Scholar]
  4. Carraway K. L., 3rd, Soltoff S. P., Diamonti A. J., Cantley L. C. 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. doi: 10.1074/jbc.270.13.7111. [DOI] [PubMed] [Google Scholar]
  5. Castagnino P., Biesova Z., Wong W. T., Fazioli F., Gill G. N., Di Fiore P. P. Direct binding of eps8 to the juxtamembrane domain of EGFR is phosphotyrosine- and SH2-independent. Oncogene. 1995 Feb 16;10(4):723–729. [PubMed] [Google Scholar]
  6. Fazioli F., Minichiello L., Matoska V., Castagnino P., Miki T., Wong W. T., Di Fiore P. P. Eps8, a substrate for the epidermal growth factor receptor kinase, enhances EGF-dependent mitogenic signals. EMBO J. 1993 Oct;12(10):3799–3808. doi: 10.1002/j.1460-2075.1993.tb06058.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fedi P., Pierce J. H., di Fiore P. P., Kraus M. H. 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. doi: 10.1128/mcb.14.1.492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fields S., Song O. A novel genetic system to detect protein-protein interactions. Nature. 1989 Jul 20;340(6230):245–246. doi: 10.1038/340245a0. [DOI] [PubMed] [Google Scholar]
  9. Galcheva-Gargova Z., Konstantinov K. N., Wu I. H., Klier F. G., Barrett T., Davis R. J. Binding of zinc finger protein ZPR1 to the epidermal growth factor receptor. Science. 1996 Jun 21;272(5269):1797–1802. doi: 10.1126/science.272.5269.1797. [DOI] [PubMed] [Google Scholar]
  10. Gamett D. C., Greene T., Wagreich A. R., Kim H. H., Koland J. G., Cerione R. A. 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. doi: 10.1074/jbc.270.32.19022. [DOI] [PubMed] [Google Scholar]
  11. Goldman R., Levy R. B., Peles E., Yarden Y. Heterodimerization of the erbB-1 and erbB-2 receptors in human breast carcinoma cells: a mechanism for receptor transregulation. Biochemistry. 1990 Dec 18;29(50):11024–11028. doi: 10.1021/bi00502a002. [DOI] [PubMed] [Google Scholar]
  12. Gullick W. J. Prevalence of aberrant expression of the epidermal growth factor receptor in human cancers. Br Med Bull. 1991 Jan;47(1):87–98. doi: 10.1093/oxfordjournals.bmb.a072464. [DOI] [PubMed] [Google Scholar]
  13. Guy P. M., Platko J. V., Cantley L. C., Cerione R. A., Carraway K. L., 3rd Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8132–8136. doi: 10.1073/pnas.91.17.8132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hellyer N. J., Kim H. H., Greaves C. H., Sierke S. L., Koland J. G. Cloning of the rat ErbB3 cDNA and characterization of the recombinant protein. Gene. 1995 Nov 20;165(2):279–284. doi: 10.1016/0378-1119(95)00436-a. [DOI] [PubMed] [Google Scholar]
  15. Holmes W. E., Sliwkowski M. X., Akita R. W., Henzel W. J., Lee J., Park J. W., Yansura D., Abadi N., Raab H., Lewis G. D. Identification of heregulin, a specific activator of p185erbB2. Science. 1992 May 22;256(5060):1205–1210. doi: 10.1126/science.256.5060.1205. [DOI] [PubMed] [Google Scholar]
  16. Jarriault S., Brou C., Logeat F., Schroeter E. H., Kopan R., Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995 Sep 28;377(6547):355–358. doi: 10.1038/377355a0. [DOI] [PubMed] [Google Scholar]
  17. Jo S. A., Zhu X., Marchionni M. A., Burden S. J. Neuregulins are concentrated at nerve-muscle synapses and activate ACh-receptor gene expression. Nature. 1995 Jan 12;373(6510):158–161. doi: 10.1038/373158a0. [DOI] [PubMed] [Google Scholar]
  18. Kim H. H., Sierke S. L., Koland J. G. Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. J Biol Chem. 1994 Oct 7;269(40):24747–24755. [PubMed] [Google Scholar]
  19. Kraus M. H., Issing W., Miki T., Popescu N. C., Aaronson S. A. 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. doi: 10.1073/pnas.86.23.9193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lamartine J., Seri M., Cinti R., Heitzmann F., Creaven M., Radomski N., Jost E., Lenoir G. M., Romeo G., Sylla B. S. Molecular cloning and mapping of a human cDNA (PA2G4) that encodes a protein highly homologous to the mouse cell cycle protein p38-2G4. Cytogenet Cell Genet. 1997;78(1):31–35. doi: 10.1159/000134621. [DOI] [PubMed] [Google Scholar]
  21. Lemoine N. R., Barnes D. M., Hollywood D. P., Hughes C. M., Smith P., Dublin E., Prigent S. A., Gullick W. J., Hurst H. C. Expression of the ERBB3 gene product in breast cancer. Br J Cancer. 1992 Dec;66(6):1116–1121. doi: 10.1038/bjc.1992.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Macías-Silva M., Abdollah S., Hoodless P. A., Pirone R., Attisano L., Wrana J. L. MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling. Cell. 1996 Dec 27;87(7):1215–1224. doi: 10.1016/s0092-8674(00)81817-6. [DOI] [PubMed] [Google Scholar]
  23. Marte B. M., Jeschke M., Graus-Porta D., Taverna D., Hofer P., Groner B., Yarden Y., Hynes N. E. Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells. Mol Endocrinol. 1995 Jan;9(1):14–23. doi: 10.1210/mend.9.1.7760847. [DOI] [PubMed] [Google Scholar]
  24. Noguchi M., Murakami M., Bennett W., Lupu R., Hui F., Jr, Harris C. C., Gerwin B. I. Biological consequences of overexpression of a transfected c-erbB-2 gene in immortalized human bronchial epithelial cells. Cancer Res. 1993 May 1;53(9):2035–2043. [PubMed] [Google Scholar]
  25. Olayioye M. A., Graus-Porta D., Beerli R. R., Rohrer J., Gay B., Hynes N. E. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol. 1998 Sep;18(9):5042–5051. doi: 10.1128/mcb.18.9.5042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Peles E., Bacus S. S., Koski R. A., Lu H. S., Wen D., Ogden S. G., Levy R. B., Yarden Y. Isolation of the neu/HER-2 stimulatory ligand: a 44 kd glycoprotein that induces differentiation of mammary tumor cells. Cell. 1992 Apr 3;69(1):205–216. doi: 10.1016/0092-8674(92)90131-u. [DOI] [PubMed] [Google Scholar]
  27. Pierce J. H., Arnstein P., DiMarco E., Artrip J., Kraus M. H., Lonardo F., Di Fiore P. P., Aaronson S. A. Oncogenic potential of erbB-2 in human mammary epithelial cells. Oncogene. 1991 Jul;6(7):1189–1194. [PubMed] [Google Scholar]
  28. Plowman G. D., Whitney G. S., Neubauer M. G., Green J. M., McDonald V. L., Todaro G. J., 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. doi: 10.1073/pnas.87.13.4905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Radomski N., Jost E. Molecular cloning of a murine cDNA encoding a novel protein, p38-2G4, which varies with the cell cycle. Exp Cell Res. 1995 Oct;220(2):434–445. doi: 10.1006/excr.1995.1335. [DOI] [PubMed] [Google Scholar]
  30. Slamon D. J., Godolphin W., Jones L. A., Holt J. A., Wong S. G., Keith D. E., Levin W. J., Stuart S. G., Udove J., Ullrich A. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707–712. doi: 10.1126/science.2470152. [DOI] [PubMed] [Google Scholar]
  31. Sliwkowski M. X., Schaefer G., Akita R. W., Lofgren J. A., Fitzpatrick V. D., Nuijens A., Fendly B. M., Cerione R. A., Vandlen R. L., Carraway K. L., 3rd Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem. 1994 May 20;269(20):14661–14665. [PubMed] [Google Scholar]
  32. Soltoff S. P., Carraway K. L., 3rd, Prigent S. A., Gullick W. G., Cantley L. C. ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 1994 Jun;14(6):3550–3558. doi: 10.1128/mcb.14.6.3550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
  34. Yamada H., Mori H., Momoi H., Nakagawa Y., Ueguchi C., Mizuno T. A fission yeast gene encoding a protein that preferentially associates with curved DNA. Yeast. 1994 Jul;10(7):883–894. doi: 10.1002/yea.320100704. [DOI] [PubMed] [Google Scholar]
  35. Yoo J. Y., Hamburger A. W. Changes in heregulin beta1 (HRGbeta1) signaling after inhibition of ErbB-2 expression in a human breast cancer cell line. Mol Cell Endocrinol. 1998 Mar 16;138(1-2):163–171. doi: 10.1016/s0303-7207(98)00004-5. [DOI] [PubMed] [Google Scholar]
  36. Yoo J. Y., Hamburger A. W. Interaction of the p23/p198 protein with ErbB-3. Gene. 1999 Mar 18;229(1-2):215–221. doi: 10.1016/s0378-1119(98)00604-0. [DOI] [PubMed] [Google Scholar]
  37. Zhang K., Sun J., Liu N., Wen D., Chang D., Thomason A., Yoshinaga S. K. Transformation of NIH 3T3 cells by HER3 or HER4 receptors requires the presence of HER1 or HER2. J Biol Chem. 1996 Feb 16;271(7):3884–3890. [PubMed] [Google Scholar]