Skip to main content
SpringerLink
Log in

Cleavage of Prolactin by Its Target Organs and the Possible Significance of this Process

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

An enzymatically cleaved form of rat prolactin (rPRL) was first described in 1980. This cleavage produces a molecule that consists of two chains of amino acids linked by a disulfide bond between two Cys residues. Reduction of that bond produces two fragments of 6 and 16 Kd. A considerable amount of information has accrued in recent years about the cleaved molecule and its 16-Kd fragment. The enzyme that cleaves the molecule is present in target tissues of PRL in rodents (e.g., mammary gland and ventral prostate), and the activity of the enzyme changes with the functional state of the mammary gland. Rat mammary PRL-cleaving activity is specific for rodent PRL, and the enzyme is localized in the stroma of that gland. The enzyme that cleaves rPRL is probably cathepsin D, and the sites of cleavage on the molecule have been identified. The cleaved form of rPRL has a high degree of activity in various assays, but it has reduced activity in radioimmunoassays. The 16-Kd fragment retains a significant degree of bioactivity in in vitro mitogenic assays, and specific binding sites for the fragment have been identified. Novel bioactivities for the cleaved form of rPRL and its 16-Kd fragment have been reported, and these molecules may account for the fact that bioassay estimates of PRL in rat serum are generally higher than are RIA measurements. Although the 16-Kd fragment has significant bioactivity, it contains only six of the fourteen residues that are thought to participate in the coupling of the intact hormone to its receptor. Cleaved rPRL is present in rat serum (but not in milk), but whether the 16-Kd fragment is formed in vivo has not yet been determined.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. O. Riddle (1963). Prolactin in vertebrate function and organization. J. Natl. Cancer Inst. 31:1039–1110.

    Google Scholar 

  2. Y. N. Sinha (1995). Structural variants of prolactin: Occurrence and physiological significance. Endocrinol. Rev. 16:354–369.

    Google Scholar 

  3. I. Mittra (1980). A novel “cleaved prolactin” in the pituitary. I. Biosynthesis, characterization and regulatory control. Biochem. Biophys. Res. Commun. 95:1750–1759.

    Google Scholar 

  4. I. Mittra (1980). A novel “cleaved prolactin” in the rat pituitary. II. In vivo mammary mitogenic activity of its N-terminal 16K moiety. Biochem. Biophys. Res. Commun. 95:1760–1767.

    Google Scholar 

  5. Y. N. Sinha and T. A. Gilligan (1984). A cleaved form of prolactin in the mouse pituitary gland: Identification and comparison of in vitro synthesis and release in strains with high and low incidences of mammary tumors. Endocrinology 114:2046–2053.

    Google Scholar 

  6. M. Andries, D. Tilemans, and C. Denef (1992). Isolation of cleaved prolactin variants that stimulate DNA synthesis in specific cell types in rat pituitary cell aggregates in culture. Biochem. J. 281:393–400.

    Google Scholar 

  7. X. Casabiell, M. C. Robertson, H. G. Friesen, and F. F. Casanueva (1989). Cleaved prolactin and its 16K fragment are generated by an acid protease. Endocrinology 125:1967–1972.

    Google Scholar 

  8. S. Meuris, M. Svoboda, M. Vilamala, J. Christophe, and C. Robyn (1983). Monomeric pituitary growth hormone and prolactin variants in man characterized by immunoperoxidase electrophoresis. FEBS Letters 154:111–115.

    Google Scholar 

  9. Y. N. Sinha, T. A. Gilligan, D. W. Lee, D. Hollingsworth, and E. Markoff (1985). Cleaved prolactin: Evidence for its occurrence in human pituitary gland and plasma. J. Clin. Endocrinol. Metab. 60:239–243.

    Google Scholar 

  10. C. Clapp, P. S. Sears, D. H. Russell, J. Richards, B. K. Levay-Young, and C. S. Nicoll (1988). Biological and immunological characterization of cleaved and 16K forms of rat prolactin. Endocrinology 122:2892–2898.

    Google Scholar 

  11. M. M. Compton and R. J. Witorsch (1983). Proteolytic fragmentation of rat prolactin by the ventral prostate gland. Prostate 4:231–238.

    Google Scholar 

  12. M. M. Compton and R. J. Witorsch (1984). Proteolytic degradation and modification of rat prolactin by subcellular fractions of the rat ventral prostate gland. Endocrinology 115:476–484.

    Google Scholar 

  13. V. L. Y. Wong, M. M. Compton, and R. J. Witorsch (1986). Proteolytic modification of rat prolactin by subcellular fractions of the lactating rat mammary gland. Biochim. Biophys. Acta 881:167–175.

    Google Scholar 

  14. C. Clapp (1987). Analysis of the proteolytic cleavage of prolactin by the mammary gland and liver of the rat: Characterization of the cleaved and 16K forms. Endocrinology 121:2055–2064.

    Google Scholar 

  15. W. J. DeVito, C. Avakian, and S. Stone (1992). Proteolytic modification of prolactin by the female rat brain. Neuroendocrinology 56:597–603.

    Google Scholar 

  16. W. J. DeVito (1988). Heterogeneity of immunoreactive prolactin in the rat brain. Biochem. Biophys. Res. Commun. 150:599–604.

    Google Scholar 

  17. C. Clapp, L. Torner, G. Gutierrez-Ospina, E. Alcantara, F. J. Lopez-Gomez, M. Nagano, P. A. Kelly, S. Mejia, M. A. Morales, and G. Martinez de la Escalera (1994). The prolactin gene is expressed in the hypothalamic-neurohypophyseal system and the protein is processed into a 14-kDa fragment with activity like 16-kDa prolactin. Proc. Nat. Acad. Sci. U.S.A. 91:10384–10388.

    Google Scholar 

  18. L. Torner, S. Mejia, F. J. Lopez-Gomez, A. Quintanar, G. Martinez de la Escalera, and C. Clapp (1995). A 14-kilodalton prolactin-like fragment is secreted by the hypothalamo-neurohypophyseal system of the rat. Endocrinology 136:5454–5460.

    Google Scholar 

  19. R. A. Baldocchi, Y.-C. Chou, and C. S. Nicoll (1994). Cleavage of rat prolactin occurs within rat mammary tissue, and the cleaved form is present in serum but not in milk. PSEBM 206:416–420.

    Google Scholar 

  20. R. A. Baldocchi, L. Tan, and C. S. Nicoll (1992). Processing of rat prolactin by rat tissue explants and serum in vitro. Endocrinology 130:1653–1659.

    Google Scholar 

  21. R. A. Baldocchi, L. Tan, D. S. King, and C. S. Nicoll (1993). Mass spectrometric analysis of the fragments produced by cleavage and reduction of rat prolactin: Evidence that the cleaving enzyme is cathepsin D. Endocrinology 133:935–938.

    Google Scholar 

  22. R. A. Baldocchi, L. Tan, Y. K. Hom, and C. S. Nicoll (1995). Comparison of the ability of normal mouse mammary tissues and mammary adenocarcinoma to cleave rat prolactin. PSEBM 208:283–287.

    Google Scholar 

  23. R. S. Vick, V. L. Y. Wong, and R. J. Witorsch (1987). Biological, immunological and biochemical characterization of cleaved prolactin generated by lactating mammary gland. Biochim. Biophys. Acta 931:196–204.

    Google Scholar 

  24. J. Zull and J. Chuang (1985). Characterization of parathyroid hormone fragments produced by cathepsin D. J. Biol. Chem. 260:1608–1613.

    Google Scholar 

  25. A. J. Barrett and J. K. McDonald (1980). Mammalian Proteases: A Glossary and Bibliography, Vol. 1: Endopeptidases. Academic Press, New York, p. 338.

    Google Scholar 

  26. G. V. Marionchenko and R. P. Khropycheva (1989). The lysosomal pathway of prolactin degradation in the mammary gland: Kinetics of hydrolysis of prolactin by cathepsin D and fragments formed. Biokhimiya 54:629–639.

    Google Scholar 

  27. C. Clapp, P. S. Sears, and C. S. Nicoll (1989). Binding studies with intact rat prolactin and a 16K fragment of the hormone. Endocrinology 125:1054–1059.

    Google Scholar 

  28. U. J. Lewis (1963). Factors that effect the fragmentation of growth hormone and prolactin by hypophyseal proteinases. J. Biol. Chem. 238:3330–3336.

    Google Scholar 

  29. R. Singh, B. Seavey, V. Rice, T. Lindsey, and U. Lewis (1974). Modified forms of human growth hormone with increased biological activities. Endocrinology 94:883–891.

    Google Scholar 

  30. J. Russell, A. B. Schneider, J. Katzhendler, K. Kowalski, and L. M. Sherwood (1979). Modification of human placental lactogen with plasmin. J. Biol. Chem. 254:2296–2301.

    Google Scholar 

  31. C. H. Li (1975). Human pituitary growth hormone: A biologically active hendekakaihekaton peptide fragment corresponding to amino-acid residues 15–125 in the hormone molecule. Proc. Nat. Acad. Sci. U.S.A. 72:3878–3882.

    Google Scholar 

  32. B. A. Doneen, H. A. Bern, and C. H. Li (1977). Biological actions of human somatotrophin and its derivatives on mouse mammary gland and teleost urinary bladder. J. Endocrinol. 73:377–382.

    Google Scholar 

  33. R. Aston and J. Ivanyi (1983). Antigenic, receptor binding and mitogenic activity of proteolytic fragments of human growth hormone. EMBO J. 2:493–494.

    Google Scholar 

  34. J. Russell, L. M. Sherwood, K. Kowalski, and A. B. Schneider (1979). Preparation of a disulfide-linked dimer of human placental lactogen fragment 1–134 with immunologic and biologic activity. Proc. Nat. Acad. Sci. U.S.A. 76:1204–1207.

    Google Scholar 

  35. J. Russell, L. M. Sherwood, K. Kowalski, and A. B. Schneider (1981). Recombinant hormones from fragments of human growth hormone and human placental lactogen. J. Biol. Chem. 256:296–300.

    Google Scholar 

  36. H. Asawaroengchai (1978). Metabolism of purified and secreted rat prolactin in vitro. Horm. Res. 9:151–156.

    Google Scholar 

  37. F. C. Leung, S. M. Russell, and C. S. Nicoll (1978). Relationship between bioassay and radioimmunoassay estimates of prolactin in rat serum. Endocrinology 103:1619–1628.

    Google Scholar 

  38. H. Asawaroengchai, S. M. Russell, and C. S. Nicoll (1978). Electrophoretically separable forms of rat prolactin with different bioassay and radioimmunoassay activities. Endocrinology 102:407–414.

    Google Scholar 

  39. C. A. Powers (1993). Anterior pituitary glandular kallikrein: A putative prolactin processing protease. Mol. Cell. Endocrinol. 90:c15–c20.

    Google Scholar 

  40. V. Goffin, K. T. Shiverick, P. A. Kelly, and J. A. Martial (1996). Sequence-function relationships within the expanding family of prolactin, growth hormone, placental lactogen, and related proteins in mammals. Endocrinol. Rev. 17:385–410.

    Google Scholar 

  41. C. S. Nicoll, G. L. Mayer, and S. M. Russell (1986). Structural features of prolactins and growth hormones that can be related to their biological properties. Endocrinol. Rev. 7:169–203.

    Google Scholar 

  42. M. Andries, G. F. M. Jacobs, D. Tilemans, and C. Denef (1996). In vitro immunoneutralization of a cleaved prolactin variant: Evidence for a local paracrine action of cleaved prolactin in the development of gonadotrophs and thyrotrophs in rat pituitary. J. Neuroendocrinol. 8:123–127.

    Google Scholar 

  43. N. Ferrara, C. Clapp, and R. Weiner (1991). The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology 129:896–900.

    Google Scholar 

  44. C. Clapp and R. Weiner (1992). A specific, high affinity, saturable binding site for the 16-kilodalton fragment of prolactin on capillary endothelial cells. Endocrinology 130:1380–1386.

    Google Scholar 

  45. M. L. Torner, C. S. Nicoll, and C. Clapp (1991). Identification of 16K prolactin in the serum of rats and mice. Progr. Endocr. Soc. U.S. (Abstract 735), p. 214.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Integrative Biology, University of California, Berkeley, California, 94720-3140

    Charles S. Nicoll

Authors
  1. Charles S. Nicoll
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicoll, C.S. Cleavage of Prolactin by Its Target Organs and the Possible Significance of this Process. J Mammary Gland Biol Neoplasia 2, 81–89 (1997). https://doi.org/10.1023/A:1026329731268

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026329731268

Search

Navigation