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.
Similar content being viewed by others
References
Kilpatrick GJ, Dautzenberg FM, Martin GR, Eglen RM. 7TM receptors: the splicing on the cake. Trends Pharmacol Sci. 1999;20:294–301.
Lopez AJ. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Ann Rev Genet 1998;32:279–305.
Smith CW, Valcarcel J. Alternative pre-mRNA splicing: the logic of combinatorial control. Trends Biochem Sci 2000;25:381–388.
Hastings ML, Krainer AR. Pre-mRNA splicing in the new millennium. Curr Opin Cell Biol 2001;13:302–309.
Minneman KP. Splice variants of G protein-coupled receptors. Mol Interven 2001;1:108–116.
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.
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.
Modrek B, Lee C. A genomic view of alternative splicing. Nat Genet 2001;30:13–19.
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.
Lee MP, Feinberg AP. Aberrant splicing but not mutations of TSG101 in human breast cancer. Cancer Res 1997;57:3131–3134.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Holmes WE, Sliwkowski MX, Akita RW, et al. Identification of heregulin, a specific activator of p185erbB2. Science 1992;256:1205–1210.
Peles E, Yarden Y. Neu and its ligands: from an oncogene to neural factors. Bioessays 1993;15:815–824.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pour PM, Kazakoff K. Effect of secretin on pancreatic carcinogenesis in the hamster model. Cancer Lett 1989;46:57–62.
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.
Romanus ME, Neal JA, Dilley WG, et al. Comparison of four provocative tests for the diagnosis of gastrinoma. Ann Surg 1983;197:608–617.
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.
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.
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.
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.
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.
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.
Rozengurt E, Walsh JH. Gastrin, CCK, signaling, and cancer. Annu Rev Physiol 2001;63:49–76.
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.
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.
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.
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.
Exton JH. Regulation of phosphoinositide phospholipases by hormones, neurotransmitters, and other agonists linked to G proteins. Ann Rev Pharmacol Toxicol 1996;36:481–509.
Nishizuka Y, Nakamura S. Lipid mediators and protein kinase C for intracellular signalling. Clin Exp Pharmacol Physiol 1995;22 Suppl 1:S202-S203.
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.
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.
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.
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.
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.
Seva C, Dickinson CJ, Yamada T. Growth-promoting effects of glycine-extended progastrin. Science 1994;265:410–412.
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.
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.
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.
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.
Koh TJ, Tidball JG. Nitric oxide synthase inhibitors reduce sarcomere addition in rat skeletal muscle. J Physiol 1999;519:189–196.
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.
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.
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.
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.
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.
Dhanasekaran N, Heasley LE, Johnson GL. G proteincoupled receptor systems involved in cell growth and oncogenesis. Endocr Rev 1995;16:259–270.
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.
Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993;60:1–41.
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.
Jaye M, Schlessinger J, Dionne CA. Fibroblast growth factor receptor tyrosine kinases: molecular analysis and signal transduction. Biochim Biophys Acta 1992;1135:185–199.
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.
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.
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.
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.
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.
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.
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.
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.
Venter JC, Adams MD, Myers EW et al. The sequence of the human genome. Science 2001;291:1304–1351.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Issue Date:
DOI: https://doi.org/10.1385/IJGC:31:1-3:31