Skip to main content
SpringerLink
Log in

Posttranslational Processing of Progastrin

  • Chapter
  • First Online:
Cellular Peptide Hormone Synthesis and Secretory Pathways

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 50))

Abstract

Gastrin and cholecystokinin (CCK) are homologous hormones with important functions in the brain and the gut. Gastrin is the main regulator of gastric acid secretion and gastric mucosal growth, whereas cholecystokinin regulates gall bladder emptying, pancreatic enzyme secretion and besides acts as a major neurotransmitter in the central and peripheral nervous systems. The tissue-specific expression of the hormones is regulated at the transcriptional level, but the posttranslational phase is also decisive and is highly complex in order to ensure accurate maturation of the prohormones in a cell specific manner. Despite the structural similarities of gastrin and CCK, there are decisive differences in the posttranslational processing and secretion schemes, suggesting that specific features in the processing may have evolved to serve specific purposes. For instance, CCK peptides circulate in low picomolar concentrations, whereas the cellular expression of gastrin is expressed at higher levels, and accordingly gastrin circulates in 10–20-fold higher concentrations. Both common cancers and the less frequent neuroendocrine tumors express the gastrin gene and prohormone. But the posttranslational processing progastrin is often greatly disturbed in neoplastic cells.

The posttranslational phase of the biogenesis of gastrin and the various progastrin products in gastrin gene-expressing tissues is now reviewed here. In addition, the individual contributions of the processing enzymes are discussed, as are structural features of progastrin that are involved in the precursor activation process. Thus, the review describes how the processing depends on the cell-specific expression of the processing enzymes and kinetics in the secretory pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andersen BN (1984) Measurement and occurrence of sulfated gastrins. Scand J Clin Lab Invest Suppl 168:5–24

    Article  PubMed  CAS  Google Scholar 

  • Andersen BN (1985) Species variation in the tyrosine sulfation of mammalian gastrins. Gen Comp Endocrinol 58:44–50

    Article  PubMed  CAS  Google Scholar 

  • Andersen BN, Abramovich D, Brand SJ, Petersen B, Rehfeld JF (1985) Complete sulfation of jejunal gastrin in the human fetus. Regul Pept 10:329–338

    Article  PubMed  CAS  Google Scholar 

  • Arvan P, Castle D (1998) Sorting and storage during secretory granule biogenesis: looking backward and looking forward. Biochem J 332(Pt 3):593–610

    PubMed  CAS  Google Scholar 

  • Brand SJ, Andersen BN, Rehfeld JF (1984a) Complete tyrosine-O-sulphation of gastrin in neonatal rat pancreas. Nature 309:456–458

    Article  PubMed  CAS  Google Scholar 

  • Brand SJ, Klarlund J, Schwartz TW, Rehfeld JF (1984b) Biosynthesis of tyrosine O-sulfated gastrins in rat antral mucosa. J Biol Chem 259:13246–13252

    PubMed  CAS  Google Scholar 

  • Bundgaard JR (2002) Heterologous expression in endocrine cells for analysis of posttranslational modifications. Methods Mol Biol 194:291–299

    PubMed  CAS  Google Scholar 

  • Bundgaard JR, Rehfeld JF (2008) Distinct linkage between post-translational processing and differential secretion of progastrin derivatives in endocrine cells. J Biol Chem 283:4014–4021

    Article  PubMed  CAS  Google Scholar 

  • Bundgaard JR, Vuust J, Rehfeld JF (1995) Tyrosine O-sulfation promotes proteolytic processing of progastrin. EMBO J 14:3073–3079

    PubMed  CAS  Google Scholar 

  • Bundgaard JR, Cowland JB, Vuust J, Rehfeld JF (1996) An efficient cellular system for mutational analysis of prohormone processing. DNA Cell Biol 15:147–157

    Article  PubMed  CAS  Google Scholar 

  • Bundgaard JR, Vuust J, Rehfeld JF (1997) New consensus features for tyrosine O-sulfation determined by mutational analysis. J Biol Chem 272:21700–21705

    Article  PubMed  CAS  Google Scholar 

  • Bundgaard JR, Birkedal H, Rehfeld JF (2004) Progastrin is directed to the regulated secretory pathway by synergistically acting basic and acidic motifs. J Biol Chem 279:5488–5493

    Article  PubMed  CAS  Google Scholar 

  • Czyzyk TA, Ning Y, Hsu MS, Peng B, Mains RE, Eipper BA, Pintar JE (2005) Deletion of peptide amidation enzymatic activity leads to edema and embryonic lethality in the mouse. Dev Biol 287:301–313

    Article  PubMed  CAS  Google Scholar 

  • Dannies PS (2001) Concentrating hormones into secretory granules: layers of control. Mol Cell Endocrinol 177:87–93

    Article  PubMed  CAS  Google Scholar 

  • Dikeakos JD, Reudelhuber TL (2007) Sending proteins to dense core secretory granules: still a lot to sort out. J Cell Biol 177:191–196

    Article  PubMed  CAS  Google Scholar 

  • Dockray GJ (1999) Topical review. Gastrin and gastric epithelial physiology. J Physiol 518(Pt 2):315–324

    Article  PubMed  CAS  Google Scholar 

  • Dockray GJ, Varro A, Desmond H, Young J, Gregory H, Gregory RA (1987) Post-translational processing of the porcine gastrin precursor by phosphorylation of the COOH-terminal fragment. J Biol Chem 262:8643–8647

    PubMed  CAS  Google Scholar 

  • Dockray G, Dimaline R, Varro A (2005) Gastrin: old hormone, new functions. Pflugers Arch 449:344–355

    Article  PubMed  CAS  Google Scholar 

  • Dufresne M, Seva C, Fourmy D (2006) Cholecystokinin and gastrin receptors. Physiol Rev 86:805–847

    Article  PubMed  CAS  Google Scholar 

  • Edkins JS (1905) On the chemical mechanism of gastric secretion. Proc Roy Soc Ser B 76:376

    Article  Google Scholar 

  • Ferrand A, Wang TC (2006) Gastrin and cancer: a review. Cancer Lett 238:15–29

    Article  PubMed  CAS  Google Scholar 

  • Fricker LD (1988) Carboxypeptidase E. Annu Rev Physiol 50:309–321

    Article  PubMed  CAS  Google Scholar 

  • Friis-Hansen L (2007) Lessons from the gastrin knockout mice. Regul Pept 139:5–22

    Article  PubMed  CAS  Google Scholar 

  • Friis-Hansen L, Rehfeld JF (1994) Ileal expression of gastrin and cholecystokinin. In search of a related hormone. FEBS Lett 343:115–119

    Article  PubMed  CAS  Google Scholar 

  • Goetze JP, Nielsen FC, Burcharth F, Rehfeld JF (2000) Closing the gastrin loop in pancreatic carcinoma: coexpression of gastrin and its receptor in solid human pancreatic adenocarcinoma. Cancer 88:2487–2494

    Article  PubMed  CAS  Google Scholar 

  • Goetze JP, Hansen CP, Rehfeld JF (2006) Antral content, secretion and peripheral metabolism of N-terminal progastrin fragments. Regul Pept 133:47–53

    Article  PubMed  CAS  Google Scholar 

  • Gregory RA, Tracy HJ, Grossman MI (1966) Isolation of two gastrins from human antral mucosa. Nature 209:583

    Article  PubMed  CAS  Google Scholar 

  • Gregory RA, Tracy HJ, Harris JI, Runswick MJ, Moore S, Kenner GW, Ramage R (1979) Minigastrin; corrected structure and synthesis. Hoppe Seylers Z Physiol Chem 360:73–80

    Article  PubMed  CAS  Google Scholar 

  • Gregory RA, Dockray GJ, Reeve JR Jr, Shively JE, Miller C (1983) Isolation from porcine antral mucosa of a hexapeptide corresponding to the C-terminal sequence of gastrin. Peptides 4:319–323

    Article  PubMed  CAS  Google Scholar 

  • Hilsted L, Rehfeld JF (1987) Alpha-carboxyamidation of antral progastrin. Relation to other post-translational modifications. J Biol Chem 262:16953–16957

    PubMed  CAS  Google Scholar 

  • Huang SC, Yu DH, Wank SA, Mantey S, Gardner JD, Jensen RT (1989) Importance of sulfation of gastrin or cholecystokinin (CCK) on affinity for gastrin and CCK receptors. Peptides 10:785–789

    Article  PubMed  CAS  Google Scholar 

  • Huttner WB (1988) Tyrosine sulfation and the secretory pathway. Annu Rev Physiol 50:363–376

    Article  PubMed  CAS  Google Scholar 

  • Ivy AC, Oldberg E (1928) A hormone mechanism for gall bladder contraction and evacuation. Am J Physol 86:599–613

    CAS  Google Scholar 

  • Jensen S, Borch K, Hilsted L, Rehfeld JF (1989) Progastrin processing during antral G-cell hypersecretion in humans. Gastroenterology 96:1063–1070

    PubMed  CAS  Google Scholar 

  • Johnsen AH (1998) Phylogeny of the cholecystokinin/gastrin family. Front Neuroendocrinol 19:73–99

    Article  PubMed  CAS  Google Scholar 

  • Johnsen AH, Rehfeld JF (1990) Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. J Biol Chem 265: 3054–3058

    PubMed  CAS  Google Scholar 

  • Kelly RB (1985) Pathways of protein secretion in eukaryotes. Science 230:25–32

    Article  PubMed  CAS  Google Scholar 

  • Lacourse KA, Friis-Hansen L, Rehfeld JF, Samuelson LC (1997) Disturbed progastrin processing in carboxypeptidase E-deficient fat mice. FEBS Lett 416:45–50

    Article  PubMed  CAS  Google Scholar 

  • Larsson LI, Rehfeld JF (1981) Pituitary gastrins occur in corticotrophs and melanotrophs. Science 213:768–770

    Article  PubMed  CAS  Google Scholar 

  • Larsson LI, Rehfeld JF, Sundler F, Håkanson R (1976) Pancreatic gastrin in foetal and neonatal rats. Nature 262:609–610

    Article  PubMed  CAS  Google Scholar 

  • Lüttichau HR, van Solinge WW, Nielsen FC, Rehfeld JF (1993) Developmental expression of the gastrin and cholecystokinin genes in rat colon. Gastroenterology 104:1092–1098

    PubMed  Google Scholar 

  • Moore KL (2003) The biology and enzymology of protein tyrosine O-sulfation. J Biol Chem 278:24243–24246

    Article  PubMed  CAS  Google Scholar 

  • Morley JS, Tracy HJ, Gregory RA (1965) Structure-function relationships in the active C-terminal tetrapeptide sequence of gastrin. Nature 207:1356–1359

    Article  PubMed  CAS  Google Scholar 

  • Müller L, Lindberg I (1999) The cell biology of the prohormone convertases PC1 and PC2. Prog Nucleic Acid Res Mol Biol 63:69–108

    Article  PubMed  Google Scholar 

  • Mutt V (1980) Cholecystokinin: isolation, structure and functions. In: Glass GBJ (ed) Gastrointestinal hormones. Raven Press, New York, pp 169–221 Ref Type: Serial (Book,Monograph)

    Google Scholar 

  • Naggert JK, Fricker LD, Varlamov O, Nishina PM, Rouille Y, Steiner DF, Carroll RJ, Paigen BJ, Leiter EH (1995) Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nat Genet 10:135–142

    Article  PubMed  CAS  Google Scholar 

  • Niehrs C, Beisswanger R, Huttner WB (1994) Protein tyrosine sulfation, 1993–an update. Chem Biol Interact 92:257–271

    Article  PubMed  CAS  Google Scholar 

  • Prigge ST, Mains RE, Eipper BA, Amzel LM (2000) New insights into copper monooxygenases and peptide amidation: structure, mechanism and function. Cell Mol Life Sci 57:1236–1259

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF (1978) Localisation of gastrins to neuro- and adenohypophysis. Nature 271:771–773

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF (1998a) Accurate measurement of cholecystokinin in plasma. Clin Chem 44:991–1001

    PubMed  CAS  Google Scholar 

  • Rehfeld JF (1998b) How to measure cholecystokinin in tissue, plasma and cerebrospinal fluid. Regul Pept 78:31–39

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF (1998c) The new biology of gastrointestinal hormones. Physiol Rev 78:1087–1108

    PubMed  CAS  Google Scholar 

  • Rehfeld JF (1991) Progastrin and its products in the cerebellum. Neuropeptides 20:239–245

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, Bardram L (1991) Processing-independent analysis (PIA)–a new diagnostic tool. Scand J Clin Lab Invest Suppl 204:9–16

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, Johnsen AH (1994) Identification of gastrin component I as gastrin-71. The largest possible bioactive progastrin product. Eur J Biochem 223:765–773

    CAS  Google Scholar 

  • Rehfeld JF, Larsson LI (1981) Pituitary gastrins. Different processing in corticotrophs and melanotrophs. J Biol Chem 256:10426–10429

    CAS  Google Scholar 

  • Rehfeld JF, Stadil F (1973) Gel filtration studies on immunoreactive gastrin in serum from Zollinger-Ellison patients. Gut 14:369–373

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, van Solinge WW (1994) The tumor biology of gastrin and cholecystokinin. Adv Cancer Res 63:295–347

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, Hilsted L, Johnsen AH (1991) Processing of antral progastrin: towards identification of gastrin components I and V. In: Håkanson R, Sundler F (eds) The stomach as an endocrine organ. Elsevier Science Publishers, Amsterdam, pp 179–195 Ref Type: Serial (Book, Monograph)

    Google Scholar 

  • Rehfeld JF, Hansen CP, Johnsen AH (1995) Post-poly(Glu) cleavage and degradation modified by O-sulfated tyrosine: a novel post-translational processing mechanism. EMBO J 14:389–396

    PubMed  CAS  Google Scholar 

  • Rehfeld JF, Lindberg I, Friis-Hansen L (2002) Progastrin processing differs in 7B2 and PC2 knockout animals: a role for 7B2 independent of action on PC2. FEBS Lett 510:89–93

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, Bundgaard JR, Goetze JP, Friis-Hansen L, Hilsted L, Johnsen AH (2004) Naming progastrin-derived peptides. Regul Pept 120:177–183

    Article  PubMed  CAS  Google Scholar 

  • Rehfeld JF, Zhu X, Norrbom C, Bundgaard JR, Johnsen AH, Nielsen JE, Vikesaa J, Stein J, Dey A, Steiner DF, Friis-Hansen L (2008) Prohormone convertases 1/3 and 2 together orchestrate the site-specific cleavages of progastrin to release gastrin-34 and gastrin-17. Biochem J 415:35–43

    Article  PubMed  CAS  Google Scholar 

  • Rengifo-Cam W, Singh P (2004) Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment. Curr Pharm Des 10:2345–2358

    Article  PubMed  CAS  Google Scholar 

  • Schalling M, Persson H, Pelto-Huikko M, Odum L, Ekman P, Gottlieb C, Hokfelt T, Rehfeld JF (1990) Expression and localization of gastrin messenger RNA and peptide in spermatogenic cells. J Clin Invest 86:660–669

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Sugano K, Aponte GW, Yamada T (1985) Identification and characterization of glycine-extended post-translational processing intermediates of progastrin in porcine stomach. J Biol Chem 260:11724–11729

    PubMed  CAS  Google Scholar 

  • Uvnäs-Wallensten K, Rehfeld JF, Larsson LI, Uvnas B (1977) Heptadecapeptide gastrin in the vagal nerve. Proc Natl Acad Sci U S A 74:5707–5710

    Article  PubMed  Google Scholar 

  • Varro A, Desmond H, Pauwels S, Gregory H, Young J, Dockray GJ (1988) The human gastrin precursor. Characterization of phosphorylated forms and fragments. Biochem J 256:951–957

    CAS  Google Scholar 

  • Vishnuvardhan D, Beinfeld MC (2000) Role of tyrosine sulfation and serine phosphorylation in the processing of procholecystokinin to amidated cholecystokinin and its secretion in transfected AtT-20 cells. Biochemistry 39:13825–13830

    Article  PubMed  CAS  Google Scholar 

  • Walsh JH, Isenberg JI, Ansfield J, Maxwell V (1976) Clearance and acid-stimulating action of human big and little gastrins in duodenal ulcer subjects. J Clin Invest 57:1125–1131

    Article  PubMed  CAS  Google Scholar 

  • Watson SA, Grabowska AM, El-Zaatari M, Takhar A (2006) Gastrin - active participant or bystander in gastric carcinogenesis? Nat Rev Cancer 6:936–946

    Article  PubMed  CAS  Google Scholar 

  • Zhou A, Webb G, Zhu X, Steiner DF (1999) Proteolytic processing in the secretory pathway. J Biol Chem 274:20745–20748

    Article  PubMed  CAS  Google Scholar 

  • Zhu X, Zhou A, Dey A, Norrbom C, Carroll R, Zhang C, Laurent V, Lindberg I, Ugleholdt R, Holst JJ, Steiner DF (2002) Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc Natl Acad Sci U S A 99:10293–10298

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, KB 3014, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Jens R. Bundgaard & Jens F. Rehfeld

Authors
  1. Jens R. Bundgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jens F. Rehfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens R. Bundgaard .

Editor information

Editors and Affiliations

  1. Rigshospitalet, Koebenhavns Universitet, Blegdamsvej 9, Koebenhavn, 2100, Denmark

    Jens F. Rehfeld

  2. Rigshospitalet, Koebenhavns Universitet, Blegdamsvej 9, Koebenhavn OE, 2100, Denmark

    Jens R. Bundgaard

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Bundgaard, J.R., Rehfeld, J.F. (2009). Posttranslational Processing of Progastrin. In: Rehfeld, J., Bundgaard, J. (eds) Cellular Peptide Hormone Synthesis and Secretory Pathways. Results and Problems in Cell Differentiation, vol 50. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_2009_34

Download citation

Publish with us

Policies and ethics

Search

Navigation