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Signaling from novel splice variants of hormone receptors in cancer

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Abstract

A number of splice variants of hormone receptors have recently been described in malignant neoplasms. Signaling by these novel receptor isoforms differ from their wild type counterparts, raising interesting questions as to possible roles in the initiation, progression, and metastatic potential of various tumors. This review summarizes recent findings on the signaling of novel variants of hormone receptors, including human HER-2/neu, the secretin receptor, the CCK-B/gastrin receptor and fibroblast growth factor receptor-2.

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References

  1. Kilpatrick GJ, Dautzenberg FM, Martin GR, Eglen RM. 7TM receptors: the splicing on the cake. Trends Pharmacol Sci. 1999;20:294–301.

    Article  PubMed  CAS  Google Scholar 

  2. Lopez AJ. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Ann Rev Genet 1998;32:279–305.

    Article  PubMed  CAS  Google Scholar 

  3. Smith CW, Valcarcel J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci 2000;25:381–388.

    Article  PubMed  CAS  Google Scholar 

  4. Hastings ML, Krainer AR. Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001;13:302–309.

    Article  PubMed  CAS  Google Scholar 

  5. Minneman KP. Splice variants of G protein-coupled receptors. Mol Interven 2001;1:108–116.

    CAS  Google Scholar 

  6. Hank J, Brett D, Aydin A, et al. Alternative splicing of human genes-more the rule than the exception? Trends Genet 1999;15:389–390.

    Article  Google Scholar 

  7. Modrek B, Resch A, Grasso C, Lee C. Genome-wide detection of alternative splicing in expressed sequences of human genes. Nucl Acid Res 2001;29:2850–2859.

    Article  CAS  Google Scholar 

  8. Modrek B, Lee C. A genomic view of alternative splicing. Nat Genet 2001;30:13–19.

    Article  Google Scholar 

  9. Stickeler E, Kittrell F, Medina D, Berget SM. Stagespecific changes in SR splicing factors and alternative splicing in mammary tumorigenesis. Oncogene 1999;18:3574–3582.

    Article  PubMed  CAS  Google Scholar 

  10. Lee MP, Feinberg AP. Aberrant splicing but not mutations of TSG101 in human breast cancer. Cancer Res 1997;57:3131–3134.

    PubMed  CAS  Google Scholar 

  11. Silberstein GB, Van Horn K, Strickland P, Roberts CT Jr, Daniel CW. Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 1997;94:8132–8137.

    Article  PubMed  CAS  Google Scholar 

  12. Jang JH, Shin KH, Park YJ, Lee RJ, McKeehan WL, Park JG. Novel transcripts of fibroblast growth factor receptor 3 reveal aberrant splicing and activation of cryptic splice sequences in colorectal cancer. Cancer Res 2000;60:4049–4052.

    PubMed  CAS  Google Scholar 

  13. Ding WQ, Kuntz S, Bohmig M, Wiedenmann B, Miller LJ. Dominant negative action of an abnormal secretin receptor arising from mRNA missplicing in a gastrinoma. Gastroenterology 2002;122:500–511.

    Article  PubMed  CAS  Google Scholar 

  14. Hellmich MR, Rui XL, Hellmich HL, Fleming RY, Evers BM, Townsend CM. Human colorectal cancers express a constitutively active cholecystokinin-B/gastrin receptor that stimulates cell growth. J Biol Chem 2000;275:32,122–32,128.

    Article  CAS  Google Scholar 

  15. Carstens RP, Eaton JV, Krigman HR, Walther PJ, Garcia-Blanco MA. Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in human prostate cancer. Oncogene 1997;15:3059–3065.

    Article  PubMed  CAS  Google Scholar 

  16. Scott GK, Robles R, Park JW, et al. A truncated intracellular HER2/neureceptor produced by alternative RNA processing affects growth of human carcinoma cells. Mol Cell Biol 1993;13:2247–2257.

    PubMed  CAS  Google Scholar 

  17. Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci USA 1999;96:10,869–10,874.

    Article  CAS  Google Scholar 

  18. Aigner A, Juhl H, Malerczyk C, Tkybusch A, Benz CC, Czubayko F. Expression of a truncated 100 kDa HER2 splice variant acts as an endogenous inhibitor of tumor cell proliferation. Oncogene 2001;20:2101–2111.

    Article  PubMed  CAS  Google Scholar 

  19. Ding WQ, Kuntz SM, Miller LJ. A Misspliced Form of the Cholecystokinin-B/Gastrin Receptor in Pancreatic Carcinoma: Role of Reduced Cellular U2AF35 and a Suboptimal 3′-Splicing Site Leading to Retention of the Fourth Intron. Cancer Res 2002;62:947–952.

    PubMed  CAS  Google Scholar 

  20. Tzahar E, Yarden Y. The ErbB-2/HER2 oncogenic receptor of adenocarcinomas: from orphanhood to multiple stromal ligands. Biochim Biophys Acta 1998;1377:M25-M37.

    PubMed  CAS  Google Scholar 

  21. Coussens L, Yang-Feng TL, Liao YC, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–1139.

    Article  PubMed  CAS  Google Scholar 

  22. Holmes WE, Sliwkowski MX, Akita RW, et al. Identification of heregulin, a specific activator of p185erbB2. Science 1992;256:1205–1210.

    Article  PubMed  CAS  Google Scholar 

  23. Peles E, Yarden Y. Neu and its ligands: from an oncogene to neural factors. Bioessays 1993;15:815–824.

    Article  PubMed  CAS  Google Scholar 

  24. Marchionni MA, Goodearl AD, Chen MS, et al. Glial growth factors are alternatively spliced erbB2 ligands expressed in the nervous system. Nature 1993;362:312–318.

    Article  PubMed  CAS  Google Scholar 

  25. Johnson GR, Kannan B, Shoyab M, Stromberg K. Amphiregulin induces tyrosine phosphorylation of the epidermal growth factor receptor and p185erbB2. Evidence that amphiregulin acts exclusively through the epidermal growth factor receptor at the surface of human epithelial cells. J Biol Chem 1993;268:2924–2931.

    PubMed  CAS  Google Scholar 

  26. Graus-Porta D, Beerli RR, Hynes NE. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling. Mol Cell Biol 1995;15:1182–1191.

    PubMed  CAS  Google Scholar 

  27. Karunagaran D, Tzahar E, Beerli RR, et al. ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. EMBO J 1996;15:254–264.

    PubMed  CAS  Google Scholar 

  28. Pietras RJ, Arboleda J, Reese DM, et al. HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 1995;10:2435–2446.

    PubMed  CAS  Google Scholar 

  29. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.

    Article  PubMed  CAS  Google Scholar 

  30. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707–712.

    Article  PubMed  CAS  Google Scholar 

  31. Ulrich CD 2nd, Holtmann M, Miller LJ. Secretin and vasoactive intestinal peptide receptors: members of a unique family of G protein-coupled receptors. Gastroenterology 1998;114:382–397.

    Article  PubMed  CAS  Google Scholar 

  32. Holtmann MH, Hadac EM, Miller LJ. Critical contributions of amino-terminal extracellular domains in agonist binding and activation of secretin and vasoactive intestinal polypeptide receptors. Studies of chimeric receptors. J Biol Chem 1995;270:14,394–14,398.

    CAS  Google Scholar 

  33. Holtmann MH, Ganguli S, Hadac EM, Dolu V, Miller LJ. Multiple extracellular loop domains contribute critical determinants for agonist binding and activation of the secretin receptor. J Biol Chem 1996;271:14,944–14,949.

    CAS  Google Scholar 

  34. Dong M, Asmann YW, Zang M, Pinon DI, Miller LJ. Identification of two pairs of spatially approximated residues within the carboxyl terminus of secretin and its receptor. J Biol Chem 2000;275:26,032–26,039.

    CAS  Google Scholar 

  35. Mannstadt M, Luck MD, Gardella TJ, Juppner H. Evidence for a ligand interaction site at the amino-terminus of the parathyroid hormone (PTH)/PTH-related protein receptor from cross-linking and mutational studies. J Biol Chem 1998;273:16,890–16,896.

    Article  CAS  Google Scholar 

  36. Pour PM, Kazakoff K. Effect of secretin on pancreatic carcinogenesis in the hamster model. Cancer Lett 1989;46:57–62.

    Article  PubMed  CAS  Google Scholar 

  37. Malagelada JR, Glanzman SL, Go VL. Laboratory diagnosis of gastrinoma. II. A prospective study of gastrin challenge tests. Mayo Clin Proc 1982;57:219–226.

    PubMed  CAS  Google Scholar 

  38. Romanus ME, Neal JA, Dilley WG, et al. Comparison of four provocative tests for the diagnosis of gastrinoma. Ann Surg 1983;197:608–617.

    Article  PubMed  CAS  Google Scholar 

  39. Frucht H, Howard JM, Slaff JI, et al. Secretin and calcium provocative tests in the Zollinger-Ellison syndrome. A prospective study. Ann Intern Med 1989;111:713–722.

    PubMed  CAS  Google Scholar 

  40. Pang RT. Ng SS. Cheng CH. Holtmann MH. Miller LJ. Chow BK. Role of N-linked glycosylation on the function and expression of the human secretin receptor. Endocrinology 1999;140:5102–5111.

    Article  PubMed  CAS  Google Scholar 

  41. Asmann YW, Dong M, Ganguli S, Hadac EM, Miller LJ. Structural insights into the amino-terminus of the secretin receptor: I. Status of cysteine and cystine residues. Mol Pharmacol 2000;58:911–919.

    PubMed  CAS  Google Scholar 

  42. Dosil M, Giot L, Davis C, Konopka JB. Dominantnegative mutations in the G-protein-coupled alpha-factor receptor map to the extracellular ends of the transmembrane segments. Mol Cell Biol 1998;18:5981–5991.

    PubMed  CAS  Google Scholar 

  43. Grosse R, Schoneberg T, Schultz G, Gudermann T. Inhibition of gonadotropin-releasing hormone receptor signaling by expression of a splice variant of the human receptor. Mol Endocrinol 1997;11:1305–1318.

    Article  PubMed  CAS  Google Scholar 

  44. Morohoshi T, Held G, Kloppel G. Exocrine pancreatic tumours and their histological classification. A study based on 167 autopsy and 97 surgical cases. Histopathology 1983;7:645–661.

    Article  PubMed  CAS  Google Scholar 

  45. Rozengurt E, Walsh JH. Gastrin, CCK, signaling, and cancer. Annu Rev Physiol 2001;63:49–76.

    Article  PubMed  CAS  Google Scholar 

  46. Todisco A, Takeuchi Y, Urumov A, Yamada J, Stepan VM, Yamada T. Molecular mechanisms for the growth factor action of gastrin. Am J Physiol 1997;273:G891-G898.

    PubMed  CAS  Google Scholar 

  47. Detjen K, Yule D, Tseng MJ, Williams JA, Logsdon CD. CCK-B receptors produce similar signals but have opposite growth effects in CHO and Swiss 3T3 cells. Am J Physiol 1997;273:C1449-C1457.

    PubMed  CAS  Google Scholar 

  48. Daulhac L, Kowalski-Chauvel A, Pradayrol L, Vaysse N, Seva C. Src-family tyrosine kinases in activation of ERK-1 and p85/p110-phosphatidylinositol 3-kinase by G/CCKB receptors. J Biol Chem 1999;274:20,657–20,663.

    Article  CAS  Google Scholar 

  49. Wang TC, Dangler CA, Chen D, et al. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 2000;118:36–47.

    Article  PubMed  CAS  Google Scholar 

  50. Exton JH. Regulation of phosphoinositide phospholipases by hormones, neurotransmitters, and other agonists linked to G proteins. Ann Rev Pharmacol Toxicol 1996;36:481–509.

    Article  CAS  Google Scholar 

  51. Nishizuka Y, Nakamura S. Lipid mediators and protein kinase C for intracellular signalling. Clin Exp Pharmacol Physiol 1995;22 Suppl 1:S202-S203.

    Article  CAS  Google Scholar 

  52. Seva C, Kowalski-Chauvel A, Blanchet JS, Vaysse N, Pradayrol L. Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex. FEBS Lett 1996;378:74–78.

    Article  PubMed  CAS  Google Scholar 

  53. Stepan VM, Dickinson CJ, del Valle J, Matsushima M, Todisco A. Cell type-specific requirement of the MAPK pathway for the growth factor action of gastrin. Am J Physiol 1999a;276:G1363-G1372.

    PubMed  CAS  Google Scholar 

  54. Hocker M, Henihan RJ, Rosewicz S, et al. Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through Raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells. J Biol Chem 1997;272:27,015–27,024.

    Article  CAS  Google Scholar 

  55. Kinoshita Y, Nakata H, Kishi K, Kawanami C, Sawada M, Chiba T. Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells. Gastroenterology 1998;115:93–100.

    Article  PubMed  CAS  Google Scholar 

  56. Seufferlein T, Withers DJ, Broad S, Herget T, Walsh JH, Rozengurt E. The human CCKB/gastrin receptor transfected into rat1 fibroblasts mediates activation of MAP kinase, p74raf-1 kinase, and mitogenesis. Cell Growth Differ 1995;6:383–393.

    PubMed  CAS  Google Scholar 

  57. Seva C, Dickinson CJ, Yamada T. Growth-promoting effects of glycine-extended progastrin. Science 1994;265:410–412.

    Article  PubMed  CAS  Google Scholar 

  58. Stepan VM, Krametter DF, Matsushima M, Todisco A, Delvalle J, Dickinson CJ. Glycine-extended gastrin regulates HEK cell growth. Am J Physiol Regulatory Integrative Comp Physiol 1999b;277:R572-R581.

    CAS  Google Scholar 

  59. Stepan VM, Sawada M, Todisco A, Dickinson CJ. Glycineextended gastrin exerts growth-promoting effects on human colon cancer cells. Mol Med 1999c;5;147–159.

    PubMed  CAS  Google Scholar 

  60. Iwase K, Evers BM, Hellmich MR, et al. Regulation of growth of human gastric cancer by gastrin and glycine-extended progastrin. Gastroenterology 1997;113:782–790.

    Article  PubMed  CAS  Google Scholar 

  61. Hollande F, Imdahl A, Mantamadiotis T, Ciccotosto GD, Shulkes A, Baldwin GS. Glycine-extended gastrin acts as an autocrine growth factor in a nontransformed colon cell line. Gastroenterology 1997;113:1576–1588.

    Article  PubMed  CAS  Google Scholar 

  62. Koh TJ, Tidball JG. Nitric oxide synthase inhibitors reduce sarcomere addition in rat skeletal muscle. J Physiol 1999;519:189–196.

    Article  PubMed  CAS  Google Scholar 

  63. Smith JP, Stock EA, Wotring MG, McLaughlin PJ, Zagon IS. Characterization of the CCK-B/gastrin-like receptor in human colon cancer. Am J Physiol 1996;271:R797-R805.

    PubMed  CAS  Google Scholar 

  64. Smith JP, Shih AH, Wotring MG, McLaughlin PJ, Zagon IS. Characterization of CCK-B/gastrin-like receptors in human gastric carcinoma. Int J Oncol 1998;12:411–419.

    PubMed  CAS  Google Scholar 

  65. Nakamura M, Sakanaka C, Aoki Y, et al. Identification of two isoforms of mouse neuropeptide Y-Y1 receptor generated by alternative splicing. Isolation, genomic structure, and functional expression of the receptors. J Biol Chem 1995;270:30,102–30,110.

    Article  CAS  Google Scholar 

  66. Elshourbagy NA, Adamou JE, Gagnon AW, Wu HL, Pullen M, Nambi P. Molecular characterization of a novel human endothelin receptor splice variant. J Biol Chem 1996;271:25,300–25,307.

    CAS  Google Scholar 

  67. Reisine T, Kong H, Raynor K, et al. Splice variant of the somatostatin receptor 2 subtype, somatostatin receptor 2B, couples to adenylyl cyclase. Mol Pharmacol 1993;44:1016–1020.

    PubMed  CAS  Google Scholar 

  68. Dhanasekaran N, Heasley LE, Johnson GL. G proteincoupled receptor systems involved in cell growth and oncogenesis. Endocr Rev 1995;16:259–270.

    Article  PubMed  CAS  Google Scholar 

  69. Arvanitakis L, Geras-Raaka E, Varma A, Gershengorn MC, Cesarman E. Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation. Nature 1997;385:347–350.

    Article  PubMed  CAS  Google Scholar 

  70. Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993;60:1–41.

    Article  PubMed  CAS  Google Scholar 

  71. Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet 1999;23:18–20.

    PubMed  CAS  Google Scholar 

  72. Jaye M, Schlessinger J, Dionne CA. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta 1992;1135:185–199.

    Article  PubMed  CAS  Google Scholar 

  73. Johnson DE, Lu J, Chen H, Werner S, Williams LT. The human fibroblast growth factor receptor genes: a common structural arrangement underlies the mechanisms for generating receptor forms that differ in their third immunoglobulin domain. Mol Cell Biol 1991;11:4627–4634.

    PubMed  CAS  Google Scholar 

  74. Yan G, Fukabori Y, McBride G, Nikolaropolous S, McKeehan WL. Exon switching and activation of stromal and embryonic fibroblast growth factor (FGF)-FGF receptor genes in prostate epithelial cells accompany stromal independence and malignancy. Mol Cell Biol 1993;13:4513–4522.

    PubMed  CAS  Google Scholar 

  75. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL. Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Res 1993;57:5369–5378.

    Google Scholar 

  76. Matsubara A, Kan M, Feng S, McKeehan WL. Inhibition of growth of malignant rat prostate tumor cells by restoration of fibroblast growth factor receptor 2. Cancer Res 1998;58:1509–1514.

    PubMed  CAS  Google Scholar 

  77. Jones RB, Carstens RP, Luo Y, McKeehan WL. 5′-and 3′-terminal nucleotides in the FGFR2 ISAR splicing element core have overlapping roles in exon IIIb activation and exon IIIc repression. Nucl Acid Res 2001;29:3557–3565.

    Article  CAS  Google Scholar 

  78. Jones RB, Wang F, Luo Y, et al. The nonsense-mediated decay pathway and mutually exclusive expression of alternatively spliced FGFR2IIIb and -IIIc mRNAs. J Biol Chem 2001;276:4158–4167.

    Article  PubMed  CAS  Google Scholar 

  79. Carstens RP, McKeehan WL, Garcia-Blanco MA. An intronic sequence element mediates both activation and repression of rat fibroblast growth factor receptor 2 pre-mRNA splicing. Mol Cell Biol 1998;18:2205–2217.

    PubMed  CAS  Google Scholar 

  80. Del Gatto-Konczak F, Olive M, Gesnel MC, Breathnach R. hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer. Mol Cell Biol 19:251–260.

  81. Venter JC, Adams MD, Myers EW et al. The sequence of the human genome. Science 2001;291:1304–1351.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Laurence J. Miller M.D..

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Ding, WQ., Miller, L.J. Signaling from novel splice variants of hormone receptors in cancer. Int J Gastrointest Canc 31, 31–39 (2002). https://doi.org/10.1385/IJGC:31:1-3:31

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