Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 3;92(14):6374–6378. doi: 10.1073/pnas.92.14.6374

Activation of mitogen-activated protein kinases by vascular endothelial growth factor and basic fibroblast growth factor in capillary endothelial cells is inhibited by the antiangiogenic factor 16-kDa N-terminal fragment of prolactin.

G D'Angelo 1, I Struman 1, J Martial 1, R I Weiner 1
PMCID: PMC41520  PMID: 7541539

Abstract

A number of factors both stimulating and inhibiting angiogenesis have been described. In the current work, we demonstrate that the angiogenic factor vascular endothelial growth factor (VEGF) activates mitogen-activated protein kinase (MAPK) as has been previously shown for basic fibroblast growth factor. The antiagiogenic factor 16-kDa N-terminal fragment of human prolactin inhibits activation of MAPK distal to autophosphorylation of the putative VEGF receptor, Flk-1, and phospholipase C-gamma. These data show that activation and inhibition of MAPK may play a central role in the control of angiogenesis.

Full text

PDF
6374

Images in this article

6375Fig. 1
on p.6375
6376Fig. 2
on p.6376
6376Fig. 3
on p.6376
6376Fig. 4
on p.6376
6376Fig. 5
on p.6376
6377Fig. 6
on p.6377
6377Fig. 7
on p.6377

Selected References

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

  1. Anderson N. G., Maller J. L., Tonks N. K., Sturgill T. W. Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase. Nature. 1990 Feb 15;343(6259):651–653. doi: 10.1038/343651a0. [DOI] [PubMed] [Google Scholar]
  2. Ausprunk D. H., Folkman J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc Res. 1977 Jul;14(1):53–65. doi: 10.1016/0026-2862(77)90141-8. [DOI] [PubMed] [Google Scholar]
  3. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5889–5892. doi: 10.1073/pnas.90.13.5889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brock T. A., Dvorak H. F., Senger D. R. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol. 1991 Jan;138(1):213–221. [PMC free article] [PubMed] [Google Scholar]
  5. Clapp C., Martial J. A., Guzman R. C., Rentier-Delure F., Weiner R. I. The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology. 1993 Sep;133(3):1292–1299. doi: 10.1210/endo.133.3.7689950. [DOI] [PubMed] [Google Scholar]
  6. Clapp C., Weiner R. I. A specific, high affinity, saturable binding site for the 16-kilodalton fragment of prolactin on capillary endothelial cells. Endocrinology. 1992 Mar;130(3):1380–1386. doi: 10.1210/endo.130.3.1311239. [DOI] [PubMed] [Google Scholar]
  7. Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
  8. Cooke N. E., Coit D., Shine J., Baxter J. D., Martial J. A. Human prolactin. cDNA structural analysis and evolutionary comparisons. J Biol Chem. 1981 Apr 25;256(8):4007–4016. [PubMed] [Google Scholar]
  9. Davis R. J. The mitogen-activated protein kinase signal transduction pathway. J Biol Chem. 1993 Jul 15;268(20):14553–14556. [PubMed] [Google Scholar]
  10. Esch F., Baird A., Ling N., Ueno N., Hill F., Denoroy L., Klepper R., Gospodarowicz D., Böhlen P., Guillemin R. Primary structure of bovine pituitary basic fibroblast growth factor (FGF) and comparison with the amino-terminal sequence of bovine brain acidic FGF. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6507–6511. doi: 10.1073/pnas.82.19.6507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ferrara N., Clapp C., Weiner R. The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells. Endocrinology. 1991 Aug;129(2):896–900. doi: 10.1210/endo-129-2-896. [DOI] [PubMed] [Google Scholar]
  12. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  13. Folkman J., Haudenschild C. C., Zetter B. R. Long-term culture of capillary endothelial cells. Proc Natl Acad Sci U S A. 1979 Oct;76(10):5217–5221. doi: 10.1073/pnas.76.10.5217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Folkman J., Klagsbrun M. Angiogenic factors. Science. 1987 Jan 23;235(4787):442–447. doi: 10.1126/science.2432664. [DOI] [PubMed] [Google Scholar]
  15. Glaser B. M., D'Amore P. A., Seppa H., Seppa S., Schiffmann E. Adult tissues contain chemoattractants for vascular endothelial cells. Nature. 1980 Dec 4;288(5790):483–484. doi: 10.1038/288483a0. [DOI] [PubMed] [Google Scholar]
  16. Good D. J., Polverini P. J., Rastinejad F., Le Beau M. M., Lemons R. S., Frazier W. A., Bouck N. P. A tumor suppressor-dependent inhibitor of angiogenesis is immunologically and functionally indistinguishable from a fragment of thrombospondin. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6624–6628. doi: 10.1073/pnas.87.17.6624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gospodarowicz D., Massoglia S., Cheng J., Fujii D. K. Effect of fibroblast growth factor and lipoproteins on the proliferation of endothelial cells derived from bovine adrenal cortex, brain cortex, and corpus luteum capillaries. J Cell Physiol. 1986 Apr;127(1):121–136. doi: 10.1002/jcp.1041270116. [DOI] [PubMed] [Google Scholar]
  18. Gotoh Y., Nishida E., Yamashita T., Hoshi M., Kawakami M., Sakai H. Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. Eur J Biochem. 1990 Nov 13;193(3):661–669. doi: 10.1111/j.1432-1033.1990.tb19384.x. [DOI] [PubMed] [Google Scholar]
  19. Johnson D. E., Williams L. T. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41. doi: 10.1016/s0065-230x(08)60821-0. [DOI] [PubMed] [Google Scholar]
  20. Lee P. L., Johnson D. E., Cousens L. S., Fried V. A., Williams L. T. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989 Jul 7;245(4913):57–60. doi: 10.1126/science.2544996. [DOI] [PubMed] [Google Scholar]
  21. Maione T. E., Gray G. S., Petro J., Hunt A. J., Donner A. L., Bauer S. I., Carson H. F., Sharpe R. J. Inhibition of angiogenesis by recombinant human platelet factor-4 and related peptides. Science. 1990 Jan 5;247(4938):77–79. doi: 10.1126/science.1688470. [DOI] [PubMed] [Google Scholar]
  22. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  23. Mohammadi M., Dionne C. A., Li W., Li N., Spivak T., Honegger A. M., Jaye M., Schlessinger J. Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis. Nature. 1992 Aug 20;358(6388):681–684. doi: 10.1038/358681a0. [DOI] [PubMed] [Google Scholar]
  24. Morrison D. K., Kaplan D. R., Escobedo J. A., Rapp U. R., Roberts T. M., Williams L. T. Direct activation of the serine/threonine kinase activity of Raf-1 through tyrosine phosphorylation by the PDGF beta-receptor. Cell. 1989 Aug 25;58(4):649–657. doi: 10.1016/0092-8674(89)90100-1. [DOI] [PubMed] [Google Scholar]
  25. O'Reilly M. S., Holmgren L., Shing Y., Chen C., Rosenthal R. A., Moses M., Lane W. S., Cao Y., Sage E. H., Folkman J. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994 Oct 21;79(2):315–328. doi: 10.1016/0092-8674(94)90200-3. [DOI] [PubMed] [Google Scholar]
  26. Olander J. V., Connolly D. T., DeLarco J. E. Specific binding of vascular permeability factor to endothelial cells. Biochem Biophys Res Commun. 1991 Feb 28;175(1):68–76. doi: 10.1016/s0006-291x(05)81201-x. [DOI] [PubMed] [Google Scholar]
  27. Pagès G., Lenormand P., L'Allemain G., Chambard J. C., Meloche S., Pouysségur J. Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8319–8323. doi: 10.1073/pnas.90.18.8319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Paris N., Rentier-Delrue F., Defontaine A., Goffin V., Lebrun J. J., Mercier L., Martial J. A. Bacterial production and purification of recombinant human prolactin. Biotechnol Appl Biochem. 1990 Aug;12(4):436–449. [PubMed] [Google Scholar]
  29. Peters K. G., Marie J., Wilson E., Ives H. E., Escobedo J., Del Rosario M., Mirda D., Williams L. T. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Ca2+ flux but not mitogenesis. Nature. 1992 Aug 20;358(6388):678–681. doi: 10.1038/358678a0. [DOI] [PubMed] [Google Scholar]
  30. Plouët J., Moukadiri H. Characterization of the receptor to vasculotropin on bovine adrenal cortex-derived capillary endothelial cells. J Biol Chem. 1990 Dec 25;265(36):22071–22074. [PubMed] [Google Scholar]
  31. Quinn T. P., Peters K. G., De Vries C., Ferrara N., Williams L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533–7537. doi: 10.1073/pnas.90.16.7533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Seetharam L., Gotoh N., Maru Y., Neufeld G., Yamaguchi S., Shibuya M. A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF. Oncogene. 1995 Jan 5;10(1):135–147. [PubMed] [Google Scholar]
  33. Shibuya M., Yamaguchi S., Yamane A., Ikeda T., Tojo A., Matsushime H., Sato M. Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. Oncogene. 1990 Apr;5(4):519–524. [PubMed] [Google Scholar]
  34. Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
  35. Thomas K. A. Fibroblast growth factors. FASEB J. 1987 Dec;1(6):434–440. doi: 10.1096/fasebj.1.6.3315806. [DOI] [PubMed] [Google Scholar]
  36. Thomas S. M., DeMarco M., D'Arcangelo G., Halegoua S., Brugge J. S. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Cell. 1992 Mar 20;68(6):1031–1040. doi: 10.1016/0092-8674(92)90075-n. [DOI] [PubMed] [Google Scholar]
  37. Ullrich A., Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990 Apr 20;61(2):203–212. doi: 10.1016/0092-8674(90)90801-k. [DOI] [PubMed] [Google Scholar]
  38. Vaisman N., Gospodarowicz D., Neufeld G. Characterization of the receptors for vascular endothelial growth factor. J Biol Chem. 1990 Nov 15;265(32):19461–19466. [PubMed] [Google Scholar]
  39. Waltenberger J., Claesson-Welsh L., Siegbahn A., Shibuya M., Heldin C. H. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. 1994 Oct 28;269(43):26988–26995. [PubMed] [Google Scholar]
  40. Wood K. W., Sarnecki C., Roberts T. M., Blenis J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell. 1992 Mar 20;68(6):1041–1050. doi: 10.1016/0092-8674(92)90076-o. [DOI] [PubMed] [Google Scholar]
  41. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES