Home LiteratureArticle Details
PMID: 12058067 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding.

Molecular biology of the cell ·Vol. 13 ·No. 6 ·2002-06-00 ·Pages 2031-44

Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A

Abstract

The ectodomain of certain transmembrane proteins can be released by the action of cell surface proteases, termed secretases. Here we have investigated how mitogen-activated protein kinases (MAPKs) control the shedding of membrane proteins. We show that extracellular signal-regulated kinase (Erk) acts as an intermediate in protein kinase C-regulated TrkA cleavage. We report that the cytosolic tail of the tumor necrosis factor alpha-converting enzyme (TACE) is phosphorylated by Erk at threonine 735. In addition, we show that Erk and TACE associate. This association is favored by Erk activation and by the presence of threonine 735. In contrast to the Erk route, the p38 MAPK was able to stimulate TrkA cleavage in cells devoid of TACE activity, indicating that other proteases are also involved in TrkA shedding. These results demonstrate that secretases are able to discriminate between the different stimuli that trigger membrane protein ectodomain cleavage and indicate that phosphorylation by MAPKs may regulate the proteolytic function of membrane secretases.

MeSH Terms
ADAM Proteins ADAM17 Protein Amino Acid Sequence Binding Sites Carrier Proteins/metabolism HeLa Cells Humans Membrane Proteins/metabolism Metalloendopeptidases/metabolism Mitogen-Activated Protein Kinases/metabolism Phosphorylation Protein Kinase C/metabolism Receptor, trkA Restriction Mapping Retroviridae Tetradecanoylphorbol Acetate/pharmacology Threonine Transfection
Chemicals
Carrier Proteins Membrane Proteins Threonine Receptor, trkA Protein Kinase C Mitogen-Activated Protein Kinases ADAM Proteins Metalloendopeptidases ADAM17 Protein ADAM17 protein, human Tetradecanoylphorbol Acetate
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Díaz-Rodríguez Elena
Instituto de Microbiología Bioquímica and Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, 37007-Salamanca, Spain.
Montero Juan Carlos
Esparís-Ogando Azucena
Yuste Laura
Pandiella Atanasio
References (41)
41 references, click to expand
  1. 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):10511-6 PMID: 10187843
  2. Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme.
    J Biol Chem. 2000 May 12;275(19):14608-14 PMID: 10799547
  3. An essential role for ectodomain shedding in mammalian development.
    Science. 1998 Nov 13;282(5392):1281-4 PMID: 9812885
  4. The search for physiological substrates of MAP and SAP kinases in mammalian cells.
    Trends Cell Biol. 1997 Sep;7(9):353-61 PMID: 17708980
  5. Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development.
    Curr Opin Cell Biol. 1998 Apr;10(2):205-19 PMID: 9561845
  6. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme.
    J Biol Chem. 2000 May 12;275(19):14598-607 PMID: 10799546
  7. 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):6962-72 PMID: 10601018
  8. Mitogen-activated protein kinase pathways.
    Curr Opin Cell Biol. 1997 Apr;9(2):180-6 PMID: 9069255
  9. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase.
    Anal Biochem. 1991 Feb 1;192(2):262-7 PMID: 1852137
  10. ADAMs: focus on the protease domain.
    Curr Opin Cell Biol. 1998 Oct;10(5):654-9 PMID: 9818177
  11. A conserved docking motif in MAP kinases common to substrates, activators and regulators.
    Nat Cell Biol. 2000 Feb;2(2):110-6 PMID: 10655591
  12. Organization and regulation of mitogen-activated protein kinase signaling pathways.
    Curr Opin Cell Biol. 1999 Apr;11(2):211-8 PMID: 10209154
  13. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.
    Cell. 1999 Apr 2;97(1):133-44 PMID: 10199409
  14. Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.
    Nature. 1997 Feb 20;385(6618):733-6 PMID: 9034191
  15. Mitogen-activated protein kinases: specific messages from ubiquitous messengers.
    Mol Cell Biol. 1999 Apr;19(4):2435-44 PMID: 10082509
  16. Membrane-anchored growth factors.
    Annu Rev Biochem. 1993;62:515-41 PMID: 8394682
  17. 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):27765-7 PMID: 9774383
  18. 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):28828-35 PMID: 10497257
  19. Cleavage of the TrkA neurotrophin receptor by multiple metalloproteases generates signalling-competent truncated forms.
    Eur J Neurosci. 1999 Apr;11(4):1421-30 PMID: 10103137
  20. Processing of tumour necrosis factor-alpha precursor by metalloproteinases.
    Nature. 1994 Aug 18;370(6490):555-7 PMID: 8052310
  21. 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):22072-80 PMID: 10419535
  22. Detection and quantification of phosphotyrosine in proteins.
    Methods Enzymol. 1983;99:387-402 PMID: 6196603
  23. Membrane proteins with soluble counterparts: role of proteolysis in the release of transmembrane proteins.
    Biochemistry. 1991 Oct 22;30(42):10065-74 PMID: 1931937
  24. Shedding of tumor necrosis factor receptors by activated human neutrophils.
    J Exp Med. 1990 Aug 1;172(2):599-607 PMID: 2165128
  25. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human.
    Physiol Rev. 1999 Jan;79(1):143-80 PMID: 9922370
  26. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
    Nature. 1997 Feb 20;385(6618):729-33 PMID: 9034190
  27. Metalloprotease-disintegrins: links to cell adhesion and cleavage of TNF alpha and Notch.
    Cell. 1997 Aug 22;90(4):589-92 PMID: 9288739
  28. C-terminal truncated forms of Met, the hepatocyte growth factor receptor.
    Mol Cell Biol. 1991 Dec;11(12):5954-62 PMID: 1944272
  29. A synthetic inhibitor of the mitogen-activated protein kinase cascade.
    Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686-9 PMID: 7644477
  30. Ligand and protein kinase C downmodulate the colony-stimulating factor 1 receptor by independent mechanisms.
    Mol Cell Biol. 1989 Jul;9(7):2890-6 PMID: 2528680
  31. Selective cleavage of the heregulin receptor ErbB-4 by protein kinase C activation.
    J Biol Chem. 1996 Aug 2;271(31):18989-95 PMID: 8702564
  32. Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease.
    Annu Rev Cell Biol. 1994;10:373-403 PMID: 7888181
  33. Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors.
    Science. 1989 Sep 15;245(4923):1238-41 PMID: 2551036
  34. Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C.
    J Biol Chem. 1994 Dec 16;269(50):31991-8 PMID: 7527401
  35. Membrane protein secretases.
    Biochem J. 1997 Jan 15;321 ( Pt 2):265-79 PMID: 9020855
  36. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing.
    Nature. 1994 Jul 21;370(6486):218-20 PMID: 8028669
  37. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor.
    Nature. 1994 Aug 18;370(6490):558-61 PMID: 8052311
  38. TrkA receptor ectodomain cleavage generates a tyrosine-phosphorylated cell-associated fragment.
    J Cell Biol. 1996 Feb;132(3):427-36 PMID: 8636219
  39. 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):7260-72 PMID: 9857183
  40. Identification of a novel inhibitor of mitogen-activated protein kinase kinase.
    J Biol Chem. 1998 Jul 17;273(29):18623-32 PMID: 9660836
  41. p38 MAP kinases: beyond the stress response.
    Trends Biochem Sci. 2000 Jun;25(6):257-60 PMID: 10838561
Article Info
Journal
Molecular biology of the cell
Abbr.
Mol Biol Cell
ISSN
1059-1524
DOI
10.1091/mbc.01-11-0561
Published
2002-06-00
Pages
2031-44
Language
English
Region
United States
NLM ID
9201390
PMCID
PMC117622
Subset
IM
External Links
PubMed source DOI: 10.1091/mbc.01-11-0561 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2