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Breast Cancer Research
Published in: Breast Cancer Research 1/2002

01-02-2002 | Review

The role of the ubiquitination-proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer

Author: Stan Lipkowitz

Published in: Breast Cancer Research | Issue 1/2002

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Abstract

Aberrant activity of growth factor receptors has been implicated in the pathogenesis of a wide variety of malignancies. The negative regulation of signaling by growth factor receptors is mediated in large part by the ubiquitination, internalization, and degradation of the activated receptor. Over the past few years, considerable insight into the mechanisms that control receptor downregulation has been gained. There are also data suggesting that mutations that lead to inhibition of downregulation of growth factor receptors could play a role in the pathogenesis of cancer. Therapies directed at enhancing the degradation of growth factor receptors offer a promising approach to the treatment of malignancies.
Literature
1.
Blume-Jensen P, Hunter T: Oncogenic kinase signalling. Nature. 2001, 411: 355-365. 10.1038/35077225.CrossRefPubMed
2.
Weissman AM: Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol. 2001, 2: 169-178. 10.1038/35056563.CrossRefPubMed
3.
Hicke L: Getting' down with ubiquitin: turning off cell-surface receptors, transporters and channels. Trends Cell Biol. 1999, 9: 107-112. 10.1016/S0962-8924(98)01491-3.CrossRefPubMed
4.
Lemmon SK, Traub LM: Sorting in the endosomal system in yeast and animal cells. Curr Opin Cell Biol. 2000, 12: 457-466. 10.1016/S0955-0674(00)00117-4.CrossRefPubMed
5.
Waterman H, Yarden Y: Molecular mechanisms underlying endocytosis and sorting of ErbB receptor tyrosine kinases. FEBS Lett. 2001, 490: 142-152. 10.1016/S0014-5793(01)02117-2.CrossRefPubMed
6.
Hershko A, Ciechanover A: The ubiquitin system. Annu Rev Biochem. 1998, 67: 425-479. 10.1146/annurev.biochem.67.1.425.CrossRefPubMed
7.
Anderson RG: The caveolae membrane system. Annu Rev Biochem. 1998, 67: 199-225. 10.1146/annurev.biochem.67.1.199.CrossRefPubMed
8.
Waugh MG, Lawson D, Hsuan JJ: Epidermal growth factor receptor activation is localized within low-buoyant density, non-caveolar membrane domains. Biochem J. 1999, 337: 591-597. 10.1042/0264-6021:3370591.CrossRefPubMedPubMedCentral
9.
Sorkin A: Endocytosis and intracellular sorting of receptor tyrosine kinases. Front Biosci. 1998, 3: d729-d738.CrossRef
10.
Thien CB, Langdon WY: Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol. 2001, 2: 294-307. 10.1038/35067100.CrossRefPubMed
11.
Waterman H, Katz M, Rubin C, Shtiegman K, Lavi S, Elson A, Jovin T, Yarden Y: A mutant EGF-receptor defective in ubiquity-lation and endocytosis unveils a role for Grb2 in negative signaling. Embo J. 2002, 21: 303-313. 10.1093/emboj/21.3.303.CrossRefPubMedPubMedCentral
12.
Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I, Lavi S, Iwai K, Reiss Y, Ciechanover A, Lipkowitz S, Yarden Y: Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell. 1999, 4: 1029-1040.CrossRefPubMed
13.
Feshchenko EA, Langdon WY, Tsygankov AY: Fyn, Yes, and Syk phosphorylation sites in c-Cbl map to the same tyrosine residues that become phosphorylated in activated T cells. J Biol Chem. 1998, 273: 8323-8331. 10.1074/jbc.273.14.8323.CrossRefPubMed
14.
Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I: Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002, 416: 183-187. 10.1038/416183a.CrossRefPubMed
15.
Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S: The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature. 2002, 416: 187-190. 10.1038/416187a.CrossRefPubMed
16.
Watanabe S, Take H, Takeda K, Yu ZX, Iwata N, Kajigaya S: Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes. Biochem Biophys Res Commun. 2000, 278: 167-174. 10.1006/bbrc.2000.3760.CrossRefPubMed
17.
Take H, Watanabe S, Takeda K, Yu ZX, Iwata N, Kajigaya S: Cloning and characterization of a novel adaptor protein, CIN85, that interacts with c-Cbl. Biochem Biophys Res Commun. 2000, 268: 321-328. 10.1006/bbrc.2000.2147.CrossRefPubMed
18.
Borinstein SC, Hyatt MA, Sykes VW, Straub RE, Lipkowitz S, Boulter J, Bogler O: SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins. Cell Signal. 2000, 12: 769-779. 10.1016/S0898-6568(00)00129-7.CrossRefPubMed
19.
Govers R, ten Broeke T, van Kerkhof P, Schwartz AL, Strous GJ: Identification of a novel ubiquitin conjugation motif, required for ligand-induced internalization of the growth hormone receptor. Embo J. 1999, 18: 28-36. 10.1093/emboj/18.1.28.CrossRefPubMedPubMedCentral
20.
Strous GJ, van Kerkhof P, Govers R, Ciechanover A, Schwartz AL: The ubiquitin conjugation system is required for ligand-induced endocytosis and degradation of the growth hormone receptor. Embo J. 1996, 15: 3806-3812.PubMedPubMedCentral
21.
van Kerkhof P, Govers R, Alves dos Santos CM, Strous GJ: Endocytosis and degradation of the growth hormone receptor are proteasome-dependent. J Biol Chem. 2000, 275: 1575-1580. 10.1074/jbc.275.3.1575.CrossRefPubMed
22.
de Melker AA, van der Horst G, Calafat J, Jansen H, Borst J: c-Cbl ubiquitinates the EGF receptor at the plasma membrane and remains receptor associated throughout the endocytic route. J Cell Sci. 2001, 114: 2167-2178.PubMed
23.
Polo S, Sigismund S, Faretta M, Guidi M, Capua MR, Bossi G, Chen H, De Camilli P, Di Fiore PP: A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature. 2002, 416: 451-455. 10.1038/416451a.CrossRefPubMed
24.
Salcini AE, Chen H, Iannolo G, De Camilli P, Di Fiore PP: Epidermal growth factor pathway substrate 15, Eps15. Int J Biochem Cell Biol. 1999, 31: 805-809. 10.1016/S1357-2725(99)00042-4.CrossRefPubMed
25.
Longva KE, Blystad FD, Stang E, Larsen AM, Johannessen LE, Madshus IH: Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol. 2002, 156: 843-854. 10.1083/jcb.200106056.CrossRefPubMedPubMedCentral
26.
Ettenberg SA, Magnifico A, Cuello M, Nau MM, Rubinstein YR, Yarden Y, Weissman AM, Lipkowitz S: Cbl-b-dependent coordinated degradation of the epidermal growth factor receptor signaling complex. J Biol Chem. 2001, 276: 27677-27684. 10.1074/jbc.M102641200.CrossRefPubMed
27.
Levkowitz G, Waterman H, Zamir E, Kam Z, Oved S, Langdon WY, Beguinot L, Geiger B, Yarden Y: c-Cbl/Sli-1 regulates endocytic sorting and ubiquitination of the epidermal growth factor receptor. Genes Dev. 1998, 12: 3663-3674.CrossRefPubMedPubMedCentral
28.
Rotin D, Staub O, Haguenauer-Tsapis R: Ubiquitination and endocytosis of plasma membrane proteins: role of Nedd4/Rsp5p family of ubiquitin-protein ligases. J Membr Biol. 2000, 176: 1-17. 10.1007/s002320001079.CrossRefPubMed
29.
Carpenter G, Cohen S: 125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts. J Cell Biol. 1976, 71: 159-171.CrossRefPubMed
30.
Swaminathan S, Amerik AY, Hochstrasser M: The Doa4 deubiquitinating enzyme is required for ubiquitin homeostasis in yeast. Mol Biol Cell. 1999, 10: 2583-2594.CrossRefPubMedPubMedCentral
31.
Bao J, Alroy I, Waterman H, Schejter ED, Brodie C, Gruenberg J, Yarden Y: Threonine phosphoylation diverts internalized EGF-receptors from a degradative pathway to the recycling endosome. J Biol Chem. 2000, 275: 26178-26186. 10.1074/jbc.M002367200.CrossRefPubMed
32.
Egan JE, Hall AB, Yatsula BA, Bar-Sagi D: The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc Natl Acad Sci USA. 2002, 99: 6041-6046. 10.1073/pnas.052090899.CrossRefPubMedPubMedCentral
33.
Andoniou CE, Thien CBF, Langdon WY: Tumour induction by activated abl involves tyrosine phosphorylation of the product of the cbl oncogene. EMBO. 1994, 13: 4515-4523.
34.
Bisson SA, Ujack EE, Robbins SM: Isolation and characterization of a novel, transforming allele of the c-Cbl proto-oncogene from a murine macrophage cell line. Oncogene. 2002, 21: 3677-3687. 10.1038/sj.onc.1205510.CrossRefPubMed
35.
Calin G, Herlea V, Barbanti-Brodano G, Negrini M: The coding region of the Bloom syndrome BLM gene and of the CBL proto-oncogene is mutated in genetically unstable sporadic gastrointestinal tumors. Cancer Res. 1998, 58: 3777-3781.PubMed
36.
Peschard P, Fournier TM, Lamorte L, Naujokas MA, Band H, Langdon WY, Park M: Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol Cell. 2001, 8: 995-1004. 10.1016/S1097-2765(01)00378-1.CrossRefPubMed
37.
Mancini A, Koch A, Wilms R, Tamura T: c-Cbl associates directly with the C-terminal tail of the receptor for the macrophage colony-stimulating factor, c-Fms, and down-modulates this receptor but not the viral oncogene v-Fms. J Biol Chem. 2002, 277: 14635-14640. 10.1074/jbc.M109214200.CrossRefPubMed
38.
Roussel MF, Shurtleff SA, Downing JR, Sherr CJ: A point mutation at tyrosine-809 in the human colony-stimulating factor 1 receptor impairs mitogenesis without abrogating tyrosine kinase activity, association with phosphatidylinositol 3-kinase, or induction of c-fos and junB genes. Proc Natl Acad Sci USA. 1990, 87: 6738-6742.CrossRefPubMedPubMedCentral
39.
Ridge SA, Worwood M, Oscier D, Jacobs A, Padua RA: FMS mutations in myelodysplastic, leukemic, and normal subjects. Proc Natl Acad Sci USA. 1990, 87: 1377-1380.CrossRefPubMedPubMedCentral
40.
Baker A, Cachia P, Ridge S, McGlynn H, Clarke R, Whittaker J, Jacobs A, Padua RA: FMS mutations in patients following cytotoxic therapy for lymphoma. Leuk Res. 1995, 19: 309-318. 10.1016/0145-2126(94)00128-W.CrossRefPubMed
41.
Baulida J, Kraus MH, Alimandi M, Di Fiore PP, Carpenter G: All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem. 1996, 271: 5251-5257. 10.1074/jbc.271.31.18989.CrossRefPubMed
42.
Pinkas-Kramarski R, Alroy I, Yarden Y: ErbB receptors and EGF-like ligands: Cell lineage determination and oncogenesis through combinatorial signaling. J Mammary Gland Biol Neo-plasia. 1997, 2: 97-107. 10.1023/A:1026343528967.CrossRef
43.
Muthuswamy SK, Gilman M, Brugge JS: Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol. 1999, 19: 6845-6857.CrossRefPubMedPubMedCentral
44.
Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA: Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999, 26: 60-70.PubMed
45.
Klapper LN, Waterman H, Sela M, Yarden Y: Tumor-inhibitory antibodies to HER-2/erbB-2 may act by recruiting c-cbl and enhancing ubiquitination of her-2. Cancer Res. 2000, 60: 3384-3388.PubMed
46.
Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L: Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. Semin Oncol. 1999, 26: 78-83.PubMed
47.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001, 344: 783-792. 10.1056/NEJM200103153441101.CrossRefPubMed
48.
Cuello M, Ettenberg SA, Clark AS, Keane MM, Posner RH, Nau MM, Dennis PA, Lipkowitz S: Down-regulation of the erbB-2 receptor by trastuzumab (herceptin) enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast and ovarian cancer cell lines that overexpress erbB-2. Cancer Res. 2001, 61: 4892-4900.PubMed
49.
Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A: p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989, 9: 1165-1172.CrossRefPubMedPubMedCentral
50.
Kumar R, Shepard HM, Mendelsohn J: Regulation of phosphorylation of the c-erbB-2/HER2 gene product by a monoclonal antibody and serum growth factor(s) in human mammary carcinoma cells. Mol Cell Biol. 1991, 11: 979-986.CrossRefPubMedPubMedCentral
51.
Blagosklonny MV: Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs. Leukemia. 2002, 16: 455-462. 10.1038/sj.leu.2402415.CrossRefPubMed
52.
Neckers L: Hsp90 inhibitors as novel cancer chemotherapeutic agents. Trends Mol Med. 2002, 8 (suppl): S55-S61. 10.1016/S1471-4914(02)02316-X.CrossRefPubMed
53.
Sepp-Lorenzino L, Ma Z, Lebwohl DE, Vinitsky A, Rosen N: Herbimycin A induces the 20 S proteasome- and ubiquitin-dependent degradation of receptor tyrosine kinases. J Biol Chem. 1995, 270: 16580-16587. 10.1074/jbc.270.28.16580.CrossRefPubMed
54.
Mimnaugh EG, Chavany C, Neckers L: Polyubiquitination and proteasomal degradation of the p185c-erbB-2 receptor protein-tyrosine kinase induced by geldanamycin. J Biol Chem. 1996, 271: 22796-22801. 10.1074/jbc.271.9.4974.CrossRefPubMed
55.
Tikhomirov O, Carpenter G: Geldanamycin induces ErbB-2 degradation by proteolytic fragmentation. J Biol Chem. 2000, 275: 26625-26631. 10.1074/jbc.M003114200.CrossRefPubMed
56.
Xu W, Mimnaugh E, Rosser MF, Nicchitta C, Marcu M, Yarden Y, Neckers L: Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem. 2001, 276: 3702-3708. 10.1074/jbc.M006864200.CrossRefPubMed
57.
Supino-Rosin L, Yoshimura A, Yarden Y, Elazar Z, Neumann D: Intracellular retention and degradation of the epidermal growth factor receptor, two distinct processes mediated by benzoquinone ansamycins. J Biol Chem. 2000, 275: 21850-21855. 10.1074/jbc.M001834200.CrossRefPubMed
58.
Citri A, Alroy I, Lavi S, Rubin C, Xu W, Grammatikakis N, Patterson C, Neckers L, Fry DW, Yarden Y: Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. Embo J. 2002, 21: 2407-2417. 10.1093/emboj/21.10.2407.CrossRefPubMedPubMedCentral
59.
Labow MA, Baim SB, Shenk T, Levine AJ: Conversion of the lac repressor into an allosterically regulated transcriptional activator for mammalian cells. Mol Cell Biol. 1990, 10: 3343-3356.CrossRefPubMedPubMedCentral
60.
Cyr DM, Hohfeld J, Patterson C: Protein quality control: U-box-containing E3 ubiquitin ligases join the fold. Trends Biochem Sci. 2002, 27: 368-375. 10.1016/S0968-0004(02)02125-4.CrossRefPubMed
61.
Pastan I: Targeted therapy of cancer with recombinant immunotoxins. Biochim Biophys Acta. 1997, 1333: C1-C6. 10.1016/S0304-419X(97)00021-8.PubMed
62.
Pastan I, Chaudhary V, FitzGerald DJ: Recombinant toxins as novel therapeutic agents. Annu Rev Biochem. 1992, 61: 331-354. 10.1146/annurev.bi.61.070192.001555.CrossRefPubMed
63.
Batra JK, Kasprzyk PG, Bird RE, Pastan I, King CR: Recombinant anti-erbB2 immunotoxins containing Pseudomonas exotoxin. Proc Natl Acad Sci USA. 1992, 89: 5867-5871.CrossRefPubMedPubMedCentral
64.
Lorimer IA, Wikstrand CJ, Batra SK, Bigner DD, Pastan I: Immunotoxins that target an oncogenic mutant epidermal growth factor receptor expressed in human tumors. Clin Cancer Res. 1995, 1: 859-864.PubMed
65.
Mixan B, Cohen BD, Bacus SS, Fell HP, Siegall CB: Betacellulin-Pseudomonas toxin fusion proteins bind but are not cytotoxic to cells expressing HER4; correlation of EGFR for cytotoxic activity. Oncogene. 1998, 16: 1209-1215. 10.1038/sj.onc.1201632.CrossRefPubMed
66.
Dean GS, Pusztai L, Xu FJ, O'Briant K, DeSombre K, Conaway M, Boyer CM, Mendelsohn J, Bast RC: Cell surface density of p185(c-erbB-2) determines susceptibility to anti-p185(c-erbB-2)-ricin A chain (RTA) immunotoxin therapy alone and in combination with anti-p170(EGFR)-RTA in ovarian cancer cells. Clin Cancer Res. 1998, 4: 2545-2550.PubMed
67.
Pai-Scherf LH, Villa J, Pearson D, Watson T, Liu E, Willingham MC, Pastan I: Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin Cancer Res. 1999, 5: 2311-2315.PubMed
Metadata
Title
The role of the ubiquitination-proteasome pathway in breast cancer: Ubiquitin mediated degradation of growth factor receptors in the pathogenesis and treatment of cancer
Author
Stan Lipkowitz
Publication date
01-02-2002
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2002
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr541

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