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
. 1991 Mar 1;88(5):1726–1730. doi: 10.1073/pnas.88.5.1726

Cleavage of the membrane precursor for transforming growth factor alpha is a regulated process.

A Pandiella 1, J Massagué 1
PMCID: PMC51097  PMID: 2000380

Abstract

Transforming growth factor alpha (TGF-alpha) is generated by cleavage of a membrane-anchored precursor protein, proTGF-alpha. ProTGF-alpha is cleaved at a slow rate and accumulates on the cell surface, thereby mediating cell-cell adhesion and mitogenic stimulation. We show here that cleavage of membrane proTGF-alpha by an elastase-like enzyme constitutes an important regulatory step in the generation of soluble TGF-alpha. Cleavage is activated in response to serum factors and tumor-promoting phorbol esters, leading to depletion of cell surface proTGF-alpha, which disperses as soluble factor. Activation of proTGF-alpha cleavage is mediated by protein kinase C-dependent and -independent mechanisms. The results demonstrate the existence of mechanisms that control the switch of TGF-alpha from a juxtacrine to a paracrine growth factor.

Full text

PDF
1726

Images in this article

1727Image
on p.1727
1727Image
on p.1727
1727Image
on p.1727
1727Image
on p.1727
1728Image
on p.1728
1728Image
on p.1728
1728Image
on p.1728
1729Image
on p.1729

Selected References

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

  1. Anderson D. M., Lyman S. D., Baird A., Wignall J. M., Eisenman J., Rauch C., March C. J., Boswell H. S., Gimpel S. D., Cosman D. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell. 1990 Oct 5;63(1):235–243. doi: 10.1016/0092-8674(90)90304-w. [DOI] [PubMed] [Google Scholar]
  2. Anklesaria P., Teixidó J., Laiho M., Pierce J. H., Greenberger J. S., Massagué J. Cell-cell adhesion mediated by binding of membrane-anchored transforming growth factor alpha to epidermal growth factor receptors promotes cell proliferation. Proc Natl Acad Sci U S A. 1990 May;87(9):3289–3293. doi: 10.1073/pnas.87.9.3289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bjorge J. D., Paterson A. J., Kudlow J. E. Phorbol ester or epidermal growth factor (EGF) stimulates the concurrent accumulation of mRNA for the EGF receptor and its ligand transforming growth factor-alpha in a breast cancer cell line. J Biol Chem. 1989 Mar 5;264(7):4021–4027. [PubMed] [Google Scholar]
  4. Blomquist M. C., Hunt L. T., Barker W. C. Vaccinia virus 19-kilodalton protein: relationship to several mammalian proteins, including two growth factors. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7363–7367. doi: 10.1073/pnas.81.23.7363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brachmann R., Lindquist P. B., Nagashima M., Kohr W., Lipari T., Napier M., Derynck R. Transmembrane TGF-alpha precursors activate EGF/TGF-alpha receptors. Cell. 1989 Feb 24;56(4):691–700. doi: 10.1016/0092-8674(89)90591-6. [DOI] [PubMed] [Google Scholar]
  6. Bringman T. S., Lindquist P. B., Derynck R. Different transforming growth factor-alpha species are derived from a glycosylated and palmitoylated transmembrane precursor. Cell. 1987 Feb 13;48(3):429–440. doi: 10.1016/0092-8674(87)90194-2. [DOI] [PubMed] [Google Scholar]
  7. Carpenter G., Cohen S. Epidermal growth factor. Annu Rev Biochem. 1979;48:193–216. doi: 10.1146/annurev.bi.48.070179.001205. [DOI] [PubMed] [Google Scholar]
  8. Coughlin S. R., Lee W. M., Williams P. W., Giels G. M., Williams L. T. c-myc gene expression is stimulated by agents that activate protein kinase C and does not account for the mitogenic effect of PDGF. Cell. 1985 Nov;43(1):243–251. doi: 10.1016/0092-8674(85)90029-7. [DOI] [PubMed] [Google Scholar]
  9. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  10. Downing J. R., Roussel M. F., Sherr C. J. Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms. Mol Cell Biol. 1989 Jul;9(7):2890–2896. doi: 10.1128/mcb.9.7.2890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Ebeling J. G., Vandenbark G. R., Kuhn L. J., Ganong B. R., Bell R. M., Niedel J. E. Diacylglycerols mimic phorbol diester induction of leukemic cell differentiation. Proc Natl Acad Sci U S A. 1985 Feb;82(3):815–819. doi: 10.1073/pnas.82.3.815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Escobedo J. A., Keating M. T., Ives H. E., Williams L. T. Platelet-derived growth factor receptors expressed by cDNA transfection couple to a diverse group of cellular responses associated with cell proliferation. J Biol Chem. 1988 Jan 25;263(3):1482–1487. [PubMed] [Google Scholar]
  13. Gray A., Dull T. J., Ullrich A. Nucleotide sequence of epidermal growth factor cDNA predicts a 128,000-molecular weight protein precursor. Nature. 1983 Jun 23;303(5919):722–725. doi: 10.1038/303722a0. [DOI] [PubMed] [Google Scholar]
  14. Huang E., Nocka K., Beier D. R., Chu T. Y., Buck J., Lahm H. W., Wellner D., Leder P., Besmer P. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990 Oct 5;63(1):225–233. doi: 10.1016/0092-8674(90)90303-v. [DOI] [PubMed] [Google Scholar]
  15. Ignotz R. A., Kelly B., Davis R. J., Massagué J. Biologically active precursor for transforming growth factor type alpha, released by retrovirally transformed cells. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6307–6311. doi: 10.1073/pnas.83.17.6307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kishimoto T. K., Jutila M. A., Berg E. L., Butcher E. C. Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. Science. 1989 Sep 15;245(4923):1238–1241. doi: 10.1126/science.2551036. [DOI] [PubMed] [Google Scholar]
  17. Kriegler M., Perez C., DeFay K., Albert I., Lu S. D. A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF. Cell. 1988 Apr 8;53(1):45–53. doi: 10.1016/0092-8674(88)90486-2. [DOI] [PubMed] [Google Scholar]
  18. Lee D. C., Rose T. M., Webb N. R., Todaro G. J. Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha. Nature. 1985 Feb 7;313(6002):489–491. doi: 10.1038/313489a0. [DOI] [PubMed] [Google Scholar]
  19. Lee M. H., Bell R. M. The lipid binding, regulatory domain of protein kinase C. A 32-kDa fragment contains the calcium- and phosphatidylserine-dependent phorbol diester binding activity. J Biol Chem. 1986 Nov 15;261(32):14867–14870. [PubMed] [Google Scholar]
  20. Linsley P. S., Hargreaves W. R., Twardzik D. R., Todaro G. J. Detection of larger polypeptides structurally and functionally related to type I transforming growth factor. Proc Natl Acad Sci U S A. 1985 Jan;82(2):356–360. doi: 10.1073/pnas.82.2.356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Luetteke N. C., Michalopoulos G. K., Teixidó J., Gilmore R., Massagué J., Lee D. C. Characterization of high molecular weight transforming growth factor alpha produced by rat hepatocellular carcinoma cells. Biochemistry. 1988 Aug 23;27(17):6487–6494. doi: 10.1021/bi00417a043. [DOI] [PubMed] [Google Scholar]
  22. Madtes D. K., Raines E. W., Sakariassen K. S., Assoian R. K., Sporn M. B., Bell G. I., Ross R. Induction of transforming growth factor-alpha in activated human alveolar macrophages. Cell. 1988 Apr 22;53(2):285–293. doi: 10.1016/0092-8674(88)90390-x. [DOI] [PubMed] [Google Scholar]
  23. Massagué J. Epidermal growth factor-like transforming growth factor. II. Interaction with epidermal growth factor receptors in human placenta membranes and A431 cells. J Biol Chem. 1983 Nov 25;258(22):13614–13620. [PubMed] [Google Scholar]
  24. Mroczkowski B., Reich M., Chen K., Bell G. I., Cohen S. Recombinant human epidermal growth factor precursor is a glycosylated membrane protein with biological activity. Mol Cell Biol. 1989 Jul;9(7):2771–2778. doi: 10.1128/mcb.9.7.2771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  26. Pittelkow M. R., Lindquist P. B., Abraham R. T., Graves-Deal R., Derynck R., Coffey R. J., Jr Induction of transforming growth factor-alpha expression in human keratinocytes by phorbol esters. J Biol Chem. 1989 Mar 25;264(9):5164–5171. [PubMed] [Google Scholar]
  27. Plowman G. D., Green J. M., McDonald V. L., Neubauer M. G., Disteche C. M., Todaro G. J., Shoyab M. The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Mol Cell Biol. 1990 May;10(5):1969–1981. doi: 10.1128/mcb.10.5.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Porteu F., Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med. 1990 Aug 1;172(2):599–607. doi: 10.1084/jem.172.2.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Powers J. C., Gupton B. F., Harley A. D., Nishino N., Whitley R. J. Specificity of porcine pancreatic elastase, human leukocyte elastase and cathepsin G. Inhibition with peptide chloromethyl ketones. Biochim Biophys Acta. 1977 Nov 23;485(1):156–166. doi: 10.1016/0005-2744(77)90203-0. [DOI] [PubMed] [Google Scholar]
  30. Raick A. N. Ultrastructural, histological, and biochemical alterations produced by 12-O-tetradecanoyl-phorbol-13-acetate on mouse epidermis and their relevance to skin tumor promotion. Cancer Res. 1973 Feb;33(2):269–286. [PubMed] [Google Scholar]
  31. Rall L. B., Scott J., Bell G. I., Crawford R. J., Penschow J. D., Niall H. D., Coghlan J. P. Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues. Nature. 1985 Jan 17;313(5999):228–231. doi: 10.1038/313228a0. [DOI] [PubMed] [Google Scholar]
  32. Rappolee D. A., Mark D., Banda M. J., Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo: analysis by mRNA phenotyping. Science. 1988 Aug 5;241(4866):708–712. doi: 10.1126/science.3041594. [DOI] [PubMed] [Google Scholar]
  33. Rettenmier C. W., Roussel M. F., Ashmun R. A., Ralph P., Price K., Sherr C. J. Synthesis of membrane-bound colony-stimulating factor 1 (CSF-1) and downmodulation of CSF-1 receptors in NIH 3T3 cells transformed by cotransfection of the human CSF-1 and c-fms (CSF-1 receptor) genes. Mol Cell Biol. 1987 Jul;7(7):2378–2387. doi: 10.1128/mcb.7.7.2378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rodriguez-Pena A., Rozengurt E. Disappearance of Ca2+-sensitive, phospholipid-dependent protein kinase activity in phorbol ester-treated 3T3 cells. Biochem Biophys Res Commun. 1984 May 16;120(3):1053–1059. doi: 10.1016/s0006-291x(84)80213-2. [DOI] [PubMed] [Google Scholar]
  35. Scott J., Urdea M., Quiroga M., Sanchez-Pescador R., Fong N., Selby M., Rutter W. J., Bell G. I. Structure of a mouse submaxillary messenger RNA encoding epidermal growth factor and seven related proteins. Science. 1983 Jul 15;221(4607):236–240. doi: 10.1126/science.6602382. [DOI] [PubMed] [Google Scholar]
  36. Stein J., Borzillo G. V., Rettenmier C. W. Direct stimulation of cells expressing receptors for macrophage colony-stimulating factor (CSF-1) by a plasma membrane-bound precursor of human CSF-1. Blood. 1990 Oct 1;76(7):1308–1314. [PubMed] [Google Scholar]
  37. Stroobant P., Rice A. P., Gullick W. J., Cheng D. J., Kerr I. M., Waterfield M. D. Purification and characterization of vaccinia virus growth factor. Cell. 1985 Aug;42(1):383–393. doi: 10.1016/s0092-8674(85)80133-1. [DOI] [PubMed] [Google Scholar]
  38. Teixido J., Wong S. T., Lee D. C., Massagué J. Generation of transforming growth factor-alpha from the cell surface by an O-glycosylation-independent multistep process. J Biol Chem. 1990 Apr 15;265(11):6410–6415. [PubMed] [Google Scholar]
  39. Teixidó J., Gilmore R., Lee D. C., Massagué J. Integral membrane glycoprotein properties of the prohormone pro-transforming growth factor-alpha. 1987 Apr 30-May 6Nature. 326(6116):883–885. doi: 10.1038/326883a0. [DOI] [PubMed] [Google Scholar]
  40. Teixidó J., Massagué J. Structural properties of a soluble bioactive precursor for transforming growth factor-alpha. J Biol Chem. 1988 Mar 15;263(8):3924–3929. [PubMed] [Google Scholar]
  41. Todaro G. J., Fryling C., De Larco J. E. Transforming growth factors produced by certain human tumor cells: polypeptides that interact with epidermal growth factor receptors. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5258–5262. doi: 10.1073/pnas.77.9.5258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wong S. T., Winchell L. F., McCune B. K., Earp H. S., Teixidó J., Massagué J., Herman B., Lee D. C. The TGF-alpha precursor expressed on the cell surface binds to the EGF receptor on adjacent cells, leading to signal transduction. Cell. 1989 Feb 10;56(3):495–506. doi: 10.1016/0092-8674(89)90252-3. [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