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PMID: 21209099 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Proprotein convertase PC7 enhances the activation of the EGF receptor pathway through processing of the EGF precursor.

The Journal of biological chemistry ·Vol. 286 ·No. 11 ·2011-03-18 ·Pages 9185-95

Rousselet E, Benjannet S, Marcinkiewicz E, Asselin MC, Lazure C, Seidah NG

Abstract

Although the processing profile of the membrane-bound epidermal growth factor precursor (pro-EGF) is tissue-specific, it has not been investigated at the cellular level nor have the cognate proteinases been defined. Among the proprotein convertases (PCs), only the membrane-bound PC7, the most ancient and conserved basic amino acid-specific PC family member, induces the processing of pro-EGF into an ∼115-kDa transmembrane form (EGF-115) at an unusual VHPR(290)↓A motif. Because site-directed mutagenesis revealed that Arg(290) is not critical, the generation of EGF-115 by PC7 is likely indirect. This was confirmed by testing a wide range of protease inhibitors, which revealed that the production of EGF-115 is most probably achieved via the activation by PC7 of a latent serine and/or cysteine protease(s). EGF-115 is more abundant at the cell surface than pro-EGF and is associated with a stronger EGF receptor (EGFR) activation, as evidenced by higher levels of phosphorylated ERK1/2. This suggests that the generation of EGF-115 represents a regulatory mechanism of juxtacrine EGFR activation. Thus, PC7 is distinct from the other PCs in its ability to enhance the activation of the cell surface EGFR.

MeSH Terms
Animals COS Cells Chlorocebus aethiops Epidermal Growth Factor/genetics,metabolism ErbB Receptors/genetics,metabolism HEK293 Cells Humans Mice Mitogen-Activated Protein Kinase 1/genetics,metabolism Mitogen-Activated Protein Kinase 3/genetics,metabolism Protease Inhibitors/pharmacology Protein Precursors/genetics,metabolism Protein Processing, Post-Translational/drug effects,physiology Subtilisins/antagonists & inhibitors,genetics,metabolism
Chemicals
Protease Inhibitors Protein Precursors Epidermal Growth Factor ErbB Receptors MAPK1 protein, human Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 PCSK7 protein, human Pcsk7 protein, mouse Subtilisins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Rousselet Estelle
Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
Benjannet Suzanne
Marcinkiewicz Edwidge
Asselin Marie-Claude
Lazure Claude
Seidah Nabil G
References (82)
82 references, click to expand
  1. Renal epidermal growth factor precursor: proteolytic processing in an in vitro cell-free system.
    Biochim Biophys Acta. 1997 Jun 5;1357(1):18-30 PMID: 9202171
  2. The epidermal growth factor precursor isolated from murine kidney membranes. Chemical characterization and biological properties.
    J Biol Chem. 1990 Sep 25;265(27):16564-70 PMID: 2398064
  3. Hypoxia-independent apoptosis in neural cells exposed to carbon monoxide in vitro.
    Brain Res. 2006 Jul 7;1098(1):1-8 PMID: 16777078
  4. Proteolytic processing of the serine protease matriptase-2: identification of the cleavage sites required for its autocatalytic release from the cell surface.
    Biochem J. 2010 Aug 15;430(1):87-95 PMID: 20518742
  5. Knock-out mouse models of proprotein convertases: unique functions or redundancy?
    Front Biosci. 2008 May 01;13:4960-71 PMID: 18508561
  6. Site-specific cleavage of BMP4 by furin, PC6, and PC7.
    J Biol Chem. 2009 Oct 2;284(40):27157-66 PMID: 19651771
  7. Proprotein convertase activity contributes to the processing of the Alzheimer's beta-amyloid precursor protein in human cells: evidence for a role of the prohormone convertase PC7 in the constitutive alpha-secretase pathway.
    J Neurochem. 1999 Nov;73(5):2056-62 PMID: 10537065
  8. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4.
    Dev Cell. 2006 Sep;11(3):313-23 PMID: 16950123
  9. The proprotein convertase PC7: unique zymogen activation and trafficking pathways.
    J Biol Chem. 2011 Jan 28;286(4):2728-38 PMID: 21075846
  10. The structure and biosynthesis of epidermal growth factor precursor.
    J Cell Sci Suppl. 1985;3:19-28 PMID: 3011823
  11. Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro.
    Thorax. 2008 Jul;63(7):621-6 PMID: 18250185
  12. Expression of full length or truncated epidermal growth factor precursor transforms NIH3T3 fibroblasts.
    Int J Oncol. 1999 Aug;15(2):281-4 PMID: 10402238
  13. Egf binding to its receptor triggers a rapid tyrosine phosphorylation of the erbB-2 protein in the mammary tumor cell line SK-BR-3.
    EMBO J. 1988 Jun;7(6):1647-51 PMID: 2901952
  14. Zebrafish ProVEGF-C expression, proteolytic processing and inhibitory effect of unprocessed ProVEGF-C during fin regeneration.
    PLoS One. 2010 Jul 02;5(7):e11438 PMID: 20625388
  15. Signaling through the epidermal growth factor receptor during the development of malignancy.
    Pharmacol Ther. 2004 Apr;102(1):37-46 PMID: 15056497
  16. Processing of epidermal growth factor in the rat submandibular gland by Kallikrein-like enzymes.
    Growth Factors. 1994;11(2):113-23 PMID: 7857656
  17. Dynasore, a cell-permeable inhibitor of dynamin.
    Dev Cell. 2006 Jun;10(6):839-50 PMID: 16740485
  18. Mouse matriptase-2: identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues.
    Biochem J. 2003 Aug 1;373(Pt 3):689-702 PMID: 12744720
  19. Biosynthesis and processing by phorbol ester of the cells surface-associated precursor form of heparin-binding EGF-like growth factor.
    Biochem Biophys Res Commun. 1994 Oct 28;204(2):592-7 PMID: 7980519
  20. In vitro elucidation of substrate specificity and bioassay of proprotein convertase 4 using intramolecularly quenched fluorogenic peptides.
    Biochem J. 2004 Jun 1;380(Pt 2):505-14 PMID: 14972029
  21. Short polybasic peptide sequences are potent inhibitors of PC5/6 and PC7: Use of positional scanning-synthetic peptide combinatorial libraries as a tool for the optimization of inhibitory sequences.
    Mol Pharmacol. 2007 Jan;71(1):323-32 PMID: 17012622
  22. alpha1-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro.
    Cancer Cell Int. 2004 Nov 21;4(1):7 PMID: 15555067
  23. The serine protease inhibitor antithrombin III inhibits LPS-mediated NF-kappaB activation by TLR-4.
    FEBS Lett. 2001 Nov 23;508(3):313-7 PMID: 11728442
  24. Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: impairment of the maturation of the E2 surface glycoprotein.
    J Biol Chem. 2008 Aug 8;283(32):21899-908 PMID: 18559340
  25. Proparathyroid hormone processing by the proprotein convertase-7: comparison with furin and assessment of modulation of parathyroid convertase messenger ribonucleic acid levels by calcium and 1,25-dihydroxyvitamin D3.
    Endocrinology. 1999 Aug;140(8):3633-42 PMID: 10433221
  26. A serine protease inhibitor prevents endoplasmic reticulum stress-induced cleavage but not transport of the membrane-bound transcription factor ATF6.
    J Biol Chem. 2003 Aug 15;278(33):31024-32 PMID: 12782636
  27. EGF precursor mRNA and membrane-associated EGF precursor protein in rat exorbital lacrimal gland.
    Am J Physiol. 1999 Mar;276(3):C734-46 PMID: 10070002
  28. Biosynthesis, distinct post-translational modifications, and functional characterization of lymphoma proprotein convertase.
    J Biol Chem. 1997 Oct 24;272(43):27116-23 PMID: 9341152
  29. Purification and characterization of the human KDEL receptor.
    Biochemistry. 1996 Aug 6;35(31):10203-9 PMID: 8756485
  30. The epidermal growth factor receptor ligands at a glance.
    J Cell Physiol. 2009 Mar;218(3):460-6 PMID: 19006176
  31. The human urinary epidermal growth factor (EGF) precursor. Isolation of a biologically active 160-kilodalton heparin-binding pro-EGF with a truncated carboxyl terminus.
    J Biol Chem. 1995 Nov 17;270(46):27954-60 PMID: 7499272
  32. The membrane fraction of homogenized rat kidney contains an enzyme that releases epidermal growth factor from the kidney membranes.
    Biochim Biophys Acta. 1991 Jul 8;1074(2):284-8 PMID: 2065081
  33. The proprotein convertases.
    Curr Opin Chem Biol. 1998 Feb;2(1):31-9 PMID: 9667917
  34. Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production.
    J Biol Chem. 2001 Apr 6;276(14):10879-87 PMID: 11152688
  35. The serpin superfamily of proteinase inhibitors: structure, function, and regulation.
    J Biol Chem. 1994 Jun 10;269(23):15957-60 PMID: 8206889
  36. Regulation of prohepcidin processing and activity by the subtilisin-like proprotein convertases Furin, PC5, PACE4 and PC7.
    Gut. 2008 Nov;57(11):1573-82 PMID: 18664504
  37. In vitro characterization of the novel proprotein convertase PC7.
    J Biol Chem. 1997 Aug 8;272(32):19672-81 PMID: 9242622
  38. The family of subtilisin/kexin like pro-protein and pro-hormone convertases: divergent or shared functions.
    Biochimie. 1994;76(3-4):197-209 PMID: 7819324
  39. Brefeldin A's effects on endosomes, lysosomes, and the TGN suggest a general mechanism for regulating organelle structure and membrane traffic.
    Cell. 1991 Nov 1;67(3):601-16 PMID: 1682055
  40. Granzyme M is a regulatory protease that inactivates proteinase inhibitor 9, an endogenous inhibitor of granzyme B.
    J Biol Chem. 2004 Dec 24;279(52):54275-82 PMID: 15494398
  41. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.
    Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):928-33 PMID: 12552133
  42. Continuous treatment of bestatin induces anti-angiogenic property in endothelial cells.
    Cancer Sci. 2007 Mar;98(3):364-72 PMID: 17270026
  43. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity.
    J Biol Chem. 1999 Nov 26;274(48):33913-20 PMID: 10567353
  44. Development of protein-based inhibitors of the proprotein of convertase SKI-1/S1P: processing of SREBP-2, ATF6, and a viral glycoprotein.
    J Biol Chem. 2004 Apr 23;279(17):17338-47 PMID: 14970232
  45. Cellular responses to EGFR inhibitors and their relevance to cancer therapy.
    Cancer Lett. 2007 Sep 8;254(2):165-77 PMID: 17367921
  46. Role of the P2 residue in determining the specificity of serpins.
    Biochemistry. 1996 Sep 3;35(35):11461-9 PMID: 8784202
  47. Recombinant human epidermal growth factor precursor is a glycosylated membrane protein with biological activity.
    Mol Cell Biol. 1989 Jul;9(7):2771-8 PMID: 2789334
  48. Implication of the proprotein convertases furin, PC5 and PC7 in the cleavage of surface glycoproteins of Hong Kong, Ebola and respiratory syncytial viruses: a comparative analysis with fluorogenic peptides.
    Biochem J. 2001 Feb 1;353(Pt 3):537-45 PMID: 11171050
  49. Occurrence of an HIV-1 gp160 endoproteolytic activity in low-density vesicles and evidence for a distinct density distribution from endogenously expressed furin and PC7/LPC convertases.
    FEBS Lett. 1999 Jul 30;456(1):97-102 PMID: 10452538
  50. Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin.
    Development. 1998 Dec;125(24):4863-76 PMID: 9811571
  51. The C-terminal cytoplasmic domain of human proEGF is a negative modulator of body and organ weights in transgenic mice.
    FEBS Lett. 2009 Apr 17;583(8):1349-57 PMID: 19328792
  52. Dynamic palmitoylation of lymphoma proprotein convertase prolongs its half-life, but is not essential for trans-Golgi network localization.
    Biochem J. 2000 Dec 15;352 Pt 3:827-33 PMID: 11104692
  53. Furin at the cutting edge: from protein traffic to embryogenesis and disease.
    Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66 PMID: 12360192
  54. The sequential cleavage of membrane anchored pro-EGF requires a membrane serine protease other than kallikrein in rat kidney.
    Regul Pept. 2004 Oct 15;122(2):119-29 PMID: 15380929
  55. Altered processing of the neurotensin/neuromedin N precursor in PC2 knock down mice: a biochemical and immunohistochemical study.
    J Neurochem. 2002 Aug;82(4):783-93 PMID: 12358783
  56. The relationship between epidermal growth factor receptors and the terminal differentiation of A431 carcinoma cells.
    Biochem Biophys Res Commun. 1986 Nov 14;140(3):837-43 PMID: 3490853
  57. Inhibition of prostasin secretion by serine protease inhibitors in the kidney.
    J Am Soc Nephrol. 2003 Jan;14(1):11-6 PMID: 12506133
  58. Proprotein and prohormone convertases: a family of subtilases generating diverse bioactive polypeptides.
    Brain Res. 1999 Nov 27;848(1-2):45-62 PMID: 10701998
  59. Alpha1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro.
    Am J Respir Cell Mol Biol. 2008 Dec;39(6):631-7 PMID: 18723439
  60. Biosynthesis and enzymatic characterization of human SKI-1/S1P and the processing of its inhibitory prosegment.
    J Biol Chem. 2000 Jan 28;275(4):2349-58 PMID: 10644685
  61. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.
    J Biol Chem. 2006 Oct 13;281(41):30561-72 PMID: 16912035
  62. Cellular cholesterol efflux mediated by cyclodextrins.
    J Biol Chem. 1995 Jul 21;270(29):17250-6 PMID: 7615524
  63. Characterization of proADAMTS5 processing by proprotein convertases.
    Int J Biochem Cell Biol. 2009 May;41(5):1116-26 PMID: 18992360
  64. In vivo functions of the proprotein convertase PC5/6 during mouse development: Gdf11 is a likely substrate.
    Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5750-5 PMID: 18378898
  65. Proprotein conversion is determined by a multiplicity of factors including convertase processing, substrate specificity, and intracellular environment. Cell type-specific processing of human prorenin by the convertase PC1.
    J Biol Chem. 1992 Jun 5;267(16):11417-23 PMID: 1597471
  66. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2.
    FASEB J. 2007 Apr;21(4):1088-98 PMID: 17242158
  67. The epidermal growth factor precursor. A calcium-binding, beta-hydroxyasparagine containing modular protein present on the surface of platelets.
    Eur J Biochem. 1999 Feb;260(1):200-7 PMID: 10091600
  68. The proprotein convertases are potential targets in the treatment of dyslipidemia.
    J Mol Med (Berl). 2007 Jul;85(7):685-96 PMID: 17351764
  69. Identification of the paired basic convertases implicated in HIV gp160 processing based on in vitro assays and expression in CD4(+) cell lines.
    J Biol Chem. 1996 Nov 29;271(48):30442-50 PMID: 8940009
  70. cDNA structure, tissue distribution, and chromosomal localization of rat PC7, a novel mammalian proprotein convertase closest to yeast kexin-like proteinases.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3388-93 PMID: 8622945
  71. EGF-stimulated tyrosine phosphorylation of p185neu: a potential model for receptor interactions.
    EMBO J. 1988 Apr;7(4):995-1001 PMID: 3261240
  72. Prostasin-dependent activation of epithelial Na+ channels by low plasmin concentrations.
    Am J Physiol Regul Integr Comp Physiol. 2009 Dec;297(6):R1733-41 PMID: 19793956
  73. Epidermal growth factor receptor activation of calpain is required for fibroblast motility and occurs via an ERK/MAP kinase signaling pathway.
    J Biol Chem. 2000 Jan 28;275(4):2390-8 PMID: 10644690
  74. Processing of proendothelin-1 by members of the subtilisin-like pro-protein convertase family.
    FEBS Lett. 2002 Jul 31;524(1-3):43-8 PMID: 12135739
  75. The cytoplasmic domain of proEGF negatively regulates motility and elastinolytic activity in thyroid carcinoma cells.
    Neoplasia. 2008 Oct;10(10):1120-30 PMID: 18813355
  76. Mouse prepro-epidermal growth factor synthesis by the kidney and other tissues.
    Nature. 1985 Jan 17-23;313(5999):228-31 PMID: 3871506
  77. Comparative functional role of PC7 and furin in the processing of the HIV envelope glycoprotein gp160.
    FEBS Lett. 1997 Mar 17;405(1):68-72 PMID: 9094426
  78. The activation and physiological functions of the proprotein convertases.
    Int J Biochem Cell Biol. 2008;40(6-7):1111-25 PMID: 18343183
  79. Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes.
    J Neurochem. 1994 Jan;62(1):27-36 PMID: 7903352
  80. A new member of the proprotein convertase gene family (LPC) is located at a chromosome translocation breakpoint in lymphomas.
    Cancer Res. 1996 Feb 1;56(3):448-51 PMID: 8564950
  81. The biosynthetic precursor of epidermal growth factor and the mechanism of its processing.
    Proc Natl Acad Sci U S A. 1979 Dec;76(12):6294-8 PMID: 316539
  82. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis.
    J Clin Invest. 2003 Jun;111(11):1723-32 PMID: 12782675
Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
1083-351X
DOI
10.1074/jbc.M110.189936
Published
2011-03-18
Epub
2011-00-05
Pages
9185-95
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC3059027
Subset
IM
Grants
Canadian Institutes of Health Research · MOP-44363 · Canada
External Links
PubMed source DOI: 10.1074/jbc.M110.189936 PMC Full Text View journal details
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