HPV16 E5 protein disrupts the c-Cbl-EGFR interaction and EGFR ubiquitination in human foreskin keratinocytes.
The E5 protein of human papillomavirus type 16 (HPV16) is a small hydrophobic protein, which localizes to the cell membrane, Golgi apparatus and endosomes. HPV16 E5 enhances the activation of the epidermal growth factor (EGFR). The activated EGFR is downregulated through the endocytic pathway, where E5 has been shown to inhibit endosomal acidification and trafficking. Ubiquitination of the activated EGFR plays a role in this downregulation. c-Cbl is a ubiquitin ligase that associates with the activated EGFR and targets it for degradation. Since E5 has been shown to form a complex with the EGFR, we tested the hypothesis that E5 affects the interaction of c-Cbl with the EGFR. We found a significant decrease of c-Cbl bound to the EGFR and of ubiquitinated EGFR in the presence of E5. E5 did not affect c-Cbl steady-state level, phosphorylation or translocation to the membrane. This novel result suggests that HPV16 E5 may, at least in part, upregulate EGFR-mediated signal transduction by inhibiting the interaction of c-Cbl with the EGFR, thereby decreasing c-Cbl-mediated degradation of the EGFR.
Zhang
Benyue
B
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
Srirangam
Anjaiah
A
Potter
David A
DA
Roman
Ann
A
D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D008297:Male; D009856:Oncogene Proteins, Viral / Q000494:pharmacology*; D027383:Papillomaviridae; D010413:Penis / Q000166:cytology; D011505:Protein-Tyrosine Kinases / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D050721:Proto-Oncogene Proteins c-cbl; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000494:pharmacology*; D015854:Up-Regulation; D000086082:Viroporin Proteins
D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D050721:Proto-Oncogene Proteins c-cbl; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C054859:oncogene protein E5, Human papillomavirus type 16; D000086082:Viroporin Proteins
Nat Rev Mol Cell Biol. 2001 Apr;2(4):294-307
11283727
J Biol Chem. 1991 May 5;266(13):8355-62
2022651
Mol Biol Cell. 2001 Jun;12(6):1897-910
11408594
J Virol. 2001 Aug;75(16):7583-91
11462030
J Cell Sci. 2001 Jun;114(Pt 11):2167-78
11493652
Am J Reprod Immunol. 2001 Oct;46(4):280-7
11642677
J Biol Chem. 1999 Oct 29;274(44):31707-12
10531381
Oncogene. 1999 Dec 13;18(53):7690-700
10618709
Semin Cancer Biol. 1999 Dec;9(6):387-95
10712885
Semin Cancer Biol. 1999 Dec;9(6):405-11
10712887
Oncogene. 2000 Dec 7;19(52):6023-32
11146554
J Virol. 2002 Jan;76(1):220-31
11739687
Oncogene. 2001 Nov 26;20(54):7866-73
11753669
Oncogene. 2001 Nov 26;20(54):7888-98
11753671
Front Biosci. 2002 Feb 1;7:d376-89
11815285
J Cell Biol. 2002 Mar 4;156(5):843-54
11864992
J Virol. 2003 Mar;77(5):2832-42
12584306
Exp Cell Res. 2003 Mar 10;284(1):99-110
12648469
J Biol Chem. 2003 Sep 12;278(37):35781-90
12829707
J Biol Chem. 2004 Aug 27;279(35):37153-62
15210722
J Virol. 1991 Sep;65(9):4860-6
1651408
Oncogene. 1992 Jan;7(1):19-25
1311062
Oncogene. 1992 Jan;7(1):27-32
1311063
Cancer Surv. 1992;12:197-217
1322242
J Virol. 1993 Aug;67(8):4521-32
8392596
J Virol. 1993 Oct;67(10):6170-8
7690419
Virology. 1994 Aug 15;203(1):73-80
8030286
J Virol. 1995 May;69(5):3185-92
7707548
J Gen Virol. 1995 May;76 ( Pt 5):1239-45
7730808
Virology. 1995 Aug 1;211(1):227-33
7645215
Oncogene. 1995 Oct 19;11(8):1561-7
7478580
J Virol. 1995 Dec;69(12):8051-6
7494320
Oncogene. 1996 Mar 7;12(5):1117-25
8649804
J Biol Chem. 1996 Jun 14;271(24):14554-9
8662998
Virology. 1996 Sep 1;223(1):251-4
8806560
Biochim Biophys Acta. 1996 Oct 9;1288(2):F55-78
8876633
J Cell Biol. 1998 May 4;141(3):647-62
9566966
Exp Cell Res. 1998 May 25;241(1):76-83
9633515
Genes Dev. 1998 Dec 1;12(23):3663-74
9851973
Clin Cancer Res. 1999 Mar;5(3):577-86
10100709
Prog Biophys Mol Biol. 1999;71(3-4):343-58
10354703
Curr Opin Cell Biol. 1999 Aug;11(4):483-8
10449328
Science. 1999 Oct 8;286(5438):309-12
10514377
Proc Natl Acad Sci U S A. 1987 Nov;84(22):7832-6
3500470
Cell. 1990 Dec 21;63(6):1129-36
2175676
Cancer Res. 2001 May 1;61(9):3837-43
11325860