Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Apr 15;363(Pt 2):211–221. doi: 10.1042/0264-6021:3630211

Mitogen-activated protein kinase-dependent and -independent routes control shedding of transmembrane growth factors through multiple secretases.

Juan Carlos Montero 1, Laura Yuste 1, Elena Díaz-Rodríguez 1, Azucena Esparís-Ogando 1, Atanasio Pandiella 1
PMCID: PMC1222469  PMID: 11931648

Abstract

Solubilization of a number of membrane proteins occurs by the action of cell-surface proteases, termed secretases. Recently, the activity of these secretases has been reported to be controlled by the extracellular signal-regulated kinases 1 and 2 (ERK1/ERK2) and the p38 mitogen-activated protein kinase (MAPK) routes. In the present paper, we show that shedding of membrane-anchored growth factors (MAGFs) may also occur through MAPK-independent routes. In Chinese-hamster ovary cells, cleavage induced by protein kinase C (PKC) stimulation was largely insensitive to inhibitors of the ERK1/ERK2 and p38 routes. Other reagents such as sorbitol or UV light stimulated MAGF cleavage independent of PKC. The action of sorbitol on cleavage was only partially prevented by the combined action of inhibitors of the p38 and ERK1/ERK2 routes, indicating that sorbitol can also stimulate shedding by MAPK-dependent and -independent routes. Studies in cells devoid of activity of the secretase tumour necrosis factor-alpha-converting enzyme (TACE) indicated that this protease had an essential role in PKC- and ERK1/ERK2-mediated shedding. However, secretases other than TACE may also cleave MAGFs since sorbitol could still induce shedding in these cells. These observations suggest that cleavage of MAGFs is a complex process in which multiple secretases, activated through different MAPK-dependent and -independent routes, are involved.

Full Text

The Full Text of this article is available as a PDF (427.2 KB).

Selected References

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

  1. Adams R. H., Porras A., Alonso G., Jones M., Vintersten K., Panelli S., Valladares A., Perez L., Klein R., Nebreda A. R. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell. 2000 Jul;6(1):109–116. [PubMed] [Google Scholar]
  2. Black R. A., Rauch C. T., Kozlosky C. J., Peschon J. J., Slack J. L., Wolfson M. F., Castner B. J., Stocking K. L., Reddy P., Srinivasan S. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 1997 Feb 20;385(6618):729–733. doi: 10.1038/385729a0. [DOI] [PubMed] [Google Scholar]
  3. Black R. A., White J. M. ADAMs: focus on the protease domain. Curr Opin Cell Biol. 1998 Oct;10(5):654–659. doi: 10.1016/s0955-0674(98)80042-2. [DOI] [PubMed] [Google Scholar]
  4. Blobel C. P. Metalloprotease-disintegrins: links to cell adhesion and cleavage of TNF alpha and Notch. Cell. 1997 Aug 22;90(4):589–592. doi: 10.1016/s0092-8674(00)80519-x. [DOI] [PubMed] [Google Scholar]
  5. Buxbaum J. D., Liu K. N., Luo Y., Slack J. L., Stocking K. L., Peschon J. J., Johnson R. S., Castner B. J., Cerretti D. P., Black R. A. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem. 1998 Oct 23;273(43):27765–27767. doi: 10.1074/jbc.273.43.27765. [DOI] [PubMed] [Google Scholar]
  6. Cabrera N., Díaz-Rodríguez E., Becker E., Martín-Zanca D., Pandiella A. TrkA receptor ectodomain cleavage generates a tyrosine-phosphorylated cell-associated fragment. J Cell Biol. 1996 Feb;132(3):427–436. doi: 10.1083/jcb.132.3.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997 Sep;7(9):353–361. doi: 10.1016/S0962-8924(97)01105-7. [DOI] [PubMed] [Google Scholar]
  8. Derynck R. The physiology of transforming growth factor-alpha. Adv Cancer Res. 1992;58:27–52. doi: 10.1016/s0065-230x(08)60289-4. [DOI] [PubMed] [Google Scholar]
  9. Dudley D. T., Pang L., Decker S. J., Bridges A. J., Saltiel A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. doi: 10.1073/pnas.92.17.7686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Díaz-Rodríguez E., Esparís-Ogando A., Montero J. C., Yuste L., Pandiella A. Stimulation of cleavage of membrane proteins by calmodulin inhibitors. Biochem J. 2000 Mar 1;346(Pt 2):359–367. [PMC free article] [PubMed] [Google Scholar]
  11. Erickson S. L., O'Shea K. S., Ghaboosi N., Loverro L., Frantz G., Bauer M., Lu L. H., Moore M. W. ErbB3 is required for normal cerebellar and cardiac development: a comparison with ErbB2-and heregulin-deficient mice. Development. 1997 Dec;124(24):4999–5011. doi: 10.1242/dev.124.24.4999. [DOI] [PubMed] [Google Scholar]
  12. Fan H., Derynck R. Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J. 1999 Dec 15;18(24):6962–6972. doi: 10.1093/emboj/18.24.6962. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Favata M. F., Horiuchi K. Y., Manos E. J., Daulerio A. J., Stradley D. A., Feeser W. S., Van Dyk D. E., Pitts W. J., Earl R. A., Hobbs F. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998 Jul 17;273(29):18623–18632. doi: 10.1074/jbc.273.29.18623. [DOI] [PubMed] [Google Scholar]
  14. Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R., Lemke G. Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor. Nature. 1995 Nov 23;378(6555):390–394. doi: 10.1038/378390a0. [DOI] [PubMed] [Google Scholar]
  15. Gearing A. J., Beckett P., Christodoulou M., Churchill M., Clements J., Davidson A. H., Drummond A. H., Galloway W. A., Gilbert R., Gordon J. L. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994 Aug 18;370(6490):555–557. doi: 10.1038/370555a0. [DOI] [PubMed] [Google Scholar]
  16. Gechtman Z., Alonso J. L., Raab G., Ingber D. E., Klagsbrun M. The shedding of membrane-anchored heparin-binding epidermal-like growth factor is regulated by the Raf/mitogen-activated protein kinase cascade and by cell adhesion and spreading. J Biol Chem. 1999 Oct 1;274(40):28828–28835. doi: 10.1074/jbc.274.40.28828. [DOI] [PubMed] [Google Scholar]
  17. Golembo M., Raz E., Shilo B. Z. The Drosophila embryonic midline is the site of Spitz processing, and induces activation of the EGF receptor in the ventral ectoderm. Development. 1996 Nov;122(11):3363–3370. doi: 10.1242/dev.122.11.3363. [DOI] [PubMed] [Google Scholar]
  18. Gutkind J. S. Cell growth control by G protein-coupled receptors: from signal transduction to signal integration. Oncogene. 1998 Sep 17;17(11 REVIEWS):1331–1342. doi: 10.1038/sj.onc.1202186. [DOI] [PubMed] [Google Scholar]
  19. Howes R., Wasserman J. D., Freeman M. In vivo analysis of Argos structure-function. Sequence requirements for inhibition of the Drosophila epidermal growth factor receptor. J Biol Chem. 1998 Feb 13;273(7):4275–4281. doi: 10.1074/jbc.273.7.4275. [DOI] [PubMed] [Google Scholar]
  20. Ip Y. T., Davis R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol. 1998 Apr;10(2):205–219. doi: 10.1016/s0955-0674(98)80143-9. [DOI] [PubMed] [Google Scholar]
  21. Izumi Y., Hirata M., Hasuwa H., Iwamoto R., Umata T., Miyado K., Tamai Y., Kurisaki T., Sehara-Fujisawa A., Ohno S. A metalloprotease-disintegrin, MDC9/meltrin-gamma/ADAM9 and PKCdelta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J. 1998 Dec 15;17(24):7260–7272. doi: 10.1093/emboj/17.24.7260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liu X., Hwang H., Cao L., Buckland M., Cunningham A., Chen J., Chien K. R., Graham R. M., Zhou M. Domain-specific gene disruption reveals critical regulation of neuregulin signaling by its cytoplasmic tail. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13024–13029. doi: 10.1073/pnas.95.22.13024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Liu X., Hwang H., Cao L., Wen D., Liu N., Graham R. M., Zhou M. Release of the neuregulin functional polypeptide requires its cytoplasmic tail. J Biol Chem. 1998 Dec 18;273(51):34335–34340. doi: 10.1074/jbc.273.51.34335. [DOI] [PubMed] [Google Scholar]
  24. Massagué J., Pandiella A. Membrane-anchored growth factors. Annu Rev Biochem. 1993;62:515–541. doi: 10.1146/annurev.bi.62.070193.002503. [DOI] [PubMed] [Google Scholar]
  25. Massagué J. Transforming growth factor-alpha. A model for membrane-anchored growth factors. J Biol Chem. 1990 Dec 15;265(35):21393–21396. [PubMed] [Google Scholar]
  26. McGeehan G. M., Becherer J. D., Bast R. C., Jr, Boyer C. M., Champion B., Connolly K. M., Conway J. G., Furdon P., Karp S., Kidao S. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature. 1994 Aug 18;370(6490):558–561. doi: 10.1038/370558a0. [DOI] [PubMed] [Google Scholar]
  27. Mellor H., Parker P. J. The extended protein kinase C superfamily. Biochem J. 1998 Jun 1;332(Pt 2):281–292. doi: 10.1042/bj3320281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Meyer D., Birchmeier C. Distinct isoforms of neuregulin are expressed in mesenchymal and neuronal cells during mouse development. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1064–1068. doi: 10.1073/pnas.91.3.1064. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Meyer D., Birchmeier C. Multiple essential functions of neuregulin in development. Nature. 1995 Nov 23;378(6555):386–390. doi: 10.1038/378386a0. [DOI] [PubMed] [Google Scholar]
  30. Meyer D., Yamaai T., Garratt A., Riethmacher-Sonnenberg E., Kane D., Theill L. E., Birchmeier C. Isoform-specific expression and function of neuregulin. Development. 1997 Sep;124(18):3575–3586. doi: 10.1242/dev.124.18.3575. [DOI] [PubMed] [Google Scholar]
  31. Mohler K. M., Sleath P. R., Fitzner J. N., Cerretti D. P., Alderson M., Kerwar S. S., Torrance D. S., Otten-Evans C., Greenstreet T., Weerawarna K. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature. 1994 Jul 21;370(6486):218–220. doi: 10.1038/370218a0. [DOI] [PubMed] [Google Scholar]
  32. Montero J. C., Yuste L., Díaz-Rodríguez E., Esparís-Ogando A., Pandiella A. Differential shedding of transmembrane neuregulin isoforms by the tumor necrosis factor-alpha-converting enzyme. Mol Cell Neurosci. 2000 Nov;16(5):631–648. doi: 10.1006/mcne.2000.0896. [DOI] [PubMed] [Google Scholar]
  33. Moss M. L., Jin S. L., Milla M. E., Bickett D. M., Burkhart W., Carter H. L., Chen W. J., Clay W. C., Didsbury J. R., Hassler D. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature. 1997 Feb 20;385(6618):733–736. doi: 10.1038/385733a0. [DOI] [PubMed] [Google Scholar]
  34. Müllberg J., Rauch C. T., Wolfson M. F., Castner B., Fitzner J. N., Otten-Evans C., Mohler K. M., Cosman D., Black R. A. Further evidence for a common mechanism for shedding of cell surface proteins. FEBS Lett. 1997 Jan 20;401(2-3):235–238. doi: 10.1016/s0014-5793(96)01480-9. [DOI] [PubMed] [Google Scholar]
  35. Nebreda A. R., Porras A. p38 MAP kinases: beyond the stress response. Trends Biochem Sci. 2000 Jun;25(6):257–260. doi: 10.1016/s0968-0004(00)01595-4. [DOI] [PubMed] [Google Scholar]
  36. Pandiella A., Bosenberg M. W., Huang E. J., Besmer P., Massagué J. Cleavage of membrane-anchored growth factors involves distinct protease activities regulated through common mechanisms. J Biol Chem. 1992 Nov 25;267(33):24028–24033. [PubMed] [Google Scholar]
  37. Pandiella A., Massagué J. Cleavage of the membrane precursor for transforming growth factor alpha is a regulated process. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1726–1730. doi: 10.1073/pnas.88.5.1726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Pandiella A., Massagué J. Multiple signals activate cleavage of the membrane transforming growth factor-alpha precursor. J Biol Chem. 1991 Mar 25;266(9):5769–5773. [PubMed] [Google Scholar]
  39. Peschon J. J., Slack J. L., Reddy P., Stocking K. L., Sunnarborg S. W., Lee D. C., Russell W. E., Castner B. J., Johnson R. S., Fitzner J. N. An essential role for ectodomain shedding in mammalian development. Science. 1998 Nov 13;282(5392):1281–1284. doi: 10.1126/science.282.5392.1281. [DOI] [PubMed] [Google Scholar]
  40. Reddy P., Slack J. L., Davis R., Cerretti D. P., Kozlosky C. J., Blanton R. A., Shows D., Peschon J. J., Black R. A. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem. 2000 May 12;275(19):14608–14614. doi: 10.1074/jbc.275.19.14608. [DOI] [PubMed] [Google Scholar]
  41. Riethmacher D., Sonnenberg-Riethmacher E., Brinkmann V., Yamaai T., Lewin G. R., Birchmeier C. Severe neuropathies in mice with targeted mutations in the ErbB3 receptor. Nature. 1997 Oct 16;389(6652):725–730. doi: 10.1038/39593. [DOI] [PubMed] [Google Scholar]
  42. Rizoli S. B., Rotstein O. D., Kapus A. Cell volume-dependent regulation of L-selectin shedding in neutrophils. A role for p38 mitogen-activated protein kinase. J Biol Chem. 1999 Jul 30;274(31):22072–22080. doi: 10.1074/jbc.274.31.22072. [DOI] [PubMed] [Google Scholar]
  43. Robinson M. J., Cobb M. H. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997 Apr;9(2):180–186. doi: 10.1016/s0955-0674(97)80061-0. [DOI] [PubMed] [Google Scholar]
  44. Sadhukhan R., Santhamma K. R., Reddy P., Peschon J. J., Black R. A., Sen I. Unaltered cleavage and secretion of angiotensin-converting enzyme in tumor necrosis factor-alpha-converting enzyme-deficient mice. J Biol Chem. 1999 Apr 9;274(15):10511–10516. doi: 10.1074/jbc.274.15.10511. [DOI] [PubMed] [Google Scholar]
  45. Schönwasser D. C., Marais R. M., Marshall C. J., Parker P. J. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol. 1998 Feb;18(2):790–798. doi: 10.1128/mcb.18.2.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Szászi K., Buday L., Kapus A. Shrinkage-induced protein tyrosine phosphorylation in Chinese hamster ovary cells. J Biol Chem. 1997 Jun 27;272(26):16670–16678. doi: 10.1074/jbc.272.26.16670. [DOI] [PubMed] [Google Scholar]
  47. Wasserman J. D., Freeman M. An autoregulatory cascade of EGF receptor signaling patterns the Drosophila egg. Cell. 1998 Oct 30;95(3):355–364. doi: 10.1016/s0092-8674(00)81767-5. [DOI] [PubMed] [Google Scholar]
  48. Widmann C., Gibson S., Jarpe M. B., Johnson G. L. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev. 1999 Jan;79(1):143–180. doi: 10.1152/physrev.1999.79.1.143. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES