Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute Leukemias

Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation

Abstract

The class III receptor tyrosine kinase FMS-like tyrosine kinase 3 (FLT3) regulates normal hematopoiesis and immunological functions. Nonetheless, constitutively active mutant FLT3 (FLT3-ITD) causally contributes to transformation and is associated with poor prognosis of acute myeloid leukemia (AML) patients. Histone deacetylase inhibitors (HDACi) can counteract deregulated gene expression profiles and decrease oncoprotein stability, which renders them candidate drugs for AML treatment. However, these drugs have pleiotropic effects and it is often unclear how they correct oncogenic transcriptomes and proteomes. We report here that treatment of AML cells with the HDACi LBH589 induces the ubiquitin-conjugating enzyme UBCH8 and degradation of FLT3-ITD. Gain- and loss-of-function approaches show that UBCH8 and the ubiquitin-ligase SIAH1 physically interact with and target FLT3-ITD for proteasomal degradation. These ubiquitinylating enzymes though have a significantly lesser effect on wild-type FLT3. Furthermore, physiological and pharmacological stimulation of FLT3 phosphorylation, inhibition of FLT3-ITD autophosphorylation and analysis of kinase-inactive FLT3-ITD revealed that tyrosine phosphorylation determines degradation of FLT3 and FLT3-ITD by the proteasome. These results provide novel insights into antileukemic activities of HDACi and position UBCH8, which have been implicated primarily in processes in the nucleus, as a previously unrecognized important modulator of FLT3-ITD stability and leukemic cell survival.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Markovic A, MacKenzie KL, Lock RB . FLT-3: a new focus in the understanding of acute leukemia. Int J Biochem Cell Biol 2005; 37: 1168–1172.

    CAS  PubMed  Google Scholar 

  2. Kikushige Y, Yoshimoto G, Miyamoto T, Iino T, Mori Y, Iwasaki H et al. Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival. J Immunol 2008; 180: 7358–7367.

    CAS  PubMed  Google Scholar 

  3. Gilliland DG, Griffin JD . The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.

    CAS  PubMed  Google Scholar 

  4. Ozeki K, Kiyoi H, Hirose Y, Iwai M, Ninomiya M, Kodera Y et al. Biologic and clinical significance of the FLT3 transcript level in acute myeloid leukemia. Blood 2004; 103: 1901–1908.

    CAS  PubMed  Google Scholar 

  5. Steffen B, Muller-Tidow C, Schwable J, Berdel WE, Serve H . The molecular pathogenesis of acute myeloid leukemia. Crit Rev Oncol Hematol 2005; 56: 195–221.

    PubMed  Google Scholar 

  6. Lee BH, Williams IR, Anastasiadou E, Boulton CL, Joseph SW, Amaral SM et al. FLT3 internal tandem duplication mutations induce myeloproliferative or lymphoid disease in a transgenic mouse model. Oncogene 2005; 24: 7882–7892.

    CAS  PubMed  Google Scholar 

  7. Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003; 3: 173–183.

    CAS  PubMed  Google Scholar 

  8. Yokota S, Kiyoi H, Nakao M, Iwai T, Misawa S, Okuda T et al. Internal tandem duplication of the FLT3 gene is preferentially seen in acute myeloid leukemia and myelodysplastic syndrome among various hematological malignancies. A study on a large series of patients and cell lines. Leukemia 1997; 11: 1605–1609.

    CAS  PubMed  Google Scholar 

  9. Meshinchi S, Appelbaum FR . Structural and functional alterations of FLT3 in acute myeloid leukemia. Clin Cancer Res 2009; 15: 4263–4269.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Paietta E, Ferrando AA, Neuberg D, Bennett JM, Racevskis J, Lazarus H et al. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood 2004; 104: 558–560.

    CAS  PubMed  Google Scholar 

  11. Van Vlierberghe P, Meijerink JP, Stam RW, van der Smissen W, van Wering ER, Beverloo HB et al. Activating FLT3 mutations in CD4+/CD8− pediatric T-cell acute lymphoblastic leukemias. Blood 2005; 106: 4414–4415.

    CAS  PubMed  Google Scholar 

  12. Schmidt-Arras D, Böhmer SA, Koch S, Müller JP, Blei L, Cornils H et al. Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality. Blood 2009; 113: 3568–3576.

    CAS  PubMed  Google Scholar 

  13. Schmidt-Arras DE, Böhmer A, Markova B, Choudhary C, Serve H, Böhmer FD . Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol Cell Biol 2005; 25: 3690–3703.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Choudhary C, Schwable J, Brandts C, Tickenbrock L, Sargin B, Kindler T et al. AML-associated Flt3 kinase domain mutations show signal transduction differences compared with Flt3 ITD mutations. Blood 2005; 106: 265–273.

    CAS  PubMed  Google Scholar 

  15. Razumovskaya E, Masson K, Khan R, Bengtsson S, Ronnstrand L . Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation. Exp Hematol 2009; 37: 979–989.

    CAS  PubMed  Google Scholar 

  16. Koch S, Jacobi A, Ryser M, Ehninger G, Thiede C . Abnormal localization and accumulation of FLT3-ITD, a mutant receptor tyrosine kinase involved in leukemogenesis. Cells Tissues Organs 2008; 188: 225–235.

    CAS  PubMed  Google Scholar 

  17. Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 2009; 36: 326–339.

    CAS  PubMed  Google Scholar 

  18. Parcells BW, Ikeda AK, Simms-Waldrip T, Moore TB, Sakamoto KM . FMS-like tyrosine kinase 3 in normal hematopoiesis and acute myeloid leukemia. Stem Cells 2006; 24: 1174–1184.

    CAS  PubMed  Google Scholar 

  19. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

    CAS  PubMed  Google Scholar 

  20. Ferrando AA, Neuberg DS, Staunton J, Loh ML, Huard C, Raimondi SC et al. Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell 2002; 1: 75–87.

    CAS  PubMed  Google Scholar 

  21. Grundler R, Miething C, Thiede C, Peschel C, Duyster J . FLT3-ITD and tyrosine kinase domain mutants induce 2 distinct phenotypes in a murine bone marrow transplantation model. Blood 2005; 105: 4792–4799.

    CAS  PubMed  Google Scholar 

  22. Mead AJ, Linch DC, Hills RK, Wheatley K, Burnett AK, Gale RE . FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 2007; 110: 1262–1270.

    CAS  PubMed  Google Scholar 

  23. Bacher U, Haferlach C, Kern W, Haferlach T, Schnittger S . Prognostic relevance of FLT3-TKD mutations in AML: the combination matters—an analysis of 3082 patients. Blood 2008; 111: 2527–2537.

    CAS  PubMed  Google Scholar 

  24. Mead AJ, Gale RE, Hills RK, Gupta M, Young BD, Burnett AK et al. Conflicting data on the prognostic significance of FLT3/TKD mutations in acute myeloid leukemia might be related to the incidence of biallelic disease. Blood 2008; 112: 444–445; author reply 445.

    CAS  PubMed  Google Scholar 

  25. Li L, Piloto O, Nguyen HB, Greenberg K, Takamiya K, Racke F et al. Knock-in of an internal tandem duplication mutation into murine FLT3 confers myeloproliferative disease in a mouse model. Blood 2008; 111: 3849–3858.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakajima H, Shibata F, Kumagai H, Shimoda K, Kitamura T . Tyk2 is dispensable for induction of myeloproliferative disease by mutant FLT3. Int J Hematol 2006; 84: 54–59.

    CAS  PubMed  Google Scholar 

  27. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG . FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002; 99: 310–318.

    CAS  PubMed  Google Scholar 

  28. Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K et al. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia. Eur J Haematol 2009; 83: 90–98.

    CAS  PubMed  Google Scholar 

  29. Stubbs MC, Kim YM, Krivtsov AV, Wright RD, Feng Z, Agarwal J et al. MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. Leukemia 2008; 22: 66–77.

    CAS  PubMed  Google Scholar 

  30. Ono R, Nakajima H, Ozaki K, Kumagai H, Kawashima T, Taki T et al. Dimerization of MLL fusion proteins and FLT3 activation synergize to induce multiple-lineage leukemogenesis. J Clin Invest 2005; 115: 919–929.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005; 115: 2159–2168.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Kottaridis PD, Gale RE, Frew ME, Harrison G, Langabeer SE, Belton AA et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001; 98: 1752–1759.

    CAS  PubMed  Google Scholar 

  33. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amaral SM, Curley DP et al. PML/RARalpha and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA 2002; 99: 8283–8288.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sohal J, Phan VT, Chan PV, Davis EM, Patel B, Kelly LM et al. A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 2003; 101: 3188–3197.

    CAS  PubMed  Google Scholar 

  35. Small D . FLT3 mutations: biology and treatment. Hematology 2006; 1: 178–184.

    Google Scholar 

  36. Sternberg DW, Licht JD . Therapeutic intervention in leukemias that express the activated fms-like tyrosine kinase 3 (FLT3): opportunities and challenges. Curr Opin Hematol 2005; 12: 7–13.

    CAS  PubMed  Google Scholar 

  37. Schmidt-Arras D, Schwable J, Böhmer FD, Serve H . Flt3 receptor tyrosine kinase as a drug target in leukemia. Curr Pharm Des 2004; 10: 1867–1883.

    CAS  PubMed  Google Scholar 

  38. Sargin B, Choudhary C, Crosetto N, Schmidt MH, Grundler R, Rensinghoff M et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 2007; 110: 1004–1012.

    CAS  PubMed  Google Scholar 

  39. Bali P, George P, Cohen P, Tao J, Guo F, Sigua C et al. Superior activity of the combination of histone deacetylase inhibitor LAQ824 and the FLT-3 kinase inhibitor PKC412 against human acute myelogenous leukemia cells with mutant FLT-3. Clin Cancer Res 2004; 10: 4991–4997.

    CAS  PubMed  Google Scholar 

  40. George P, Bali P, Annavarapu S, Scuto A, Fiskus W, Guo F et al. Combination of the histone deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active against human CML-BC cells and AML cells with activating mutation of FLT-3. Blood 2005; 105: 1768–1776.

    CAS  PubMed  Google Scholar 

  41. Robinson LJ, Xue J, Corey SJ . Src family tyrosine kinases are activated by Flt3 and are involved in the proliferative effects of leukemia-associated Flt3 mutations. Exp Hematol 2005; 33: 469–479.

    CAS  PubMed  Google Scholar 

  42. Buchwald M, Krämer OH, Heinzel T . HDACi—targets beyond chromatin. Cancer Lett 2009; 280: 160–167.

    CAS  PubMed  Google Scholar 

  43. Jung T, Catalgol B, Grune T . The proteasomal system. Mol Aspects Med 2009; 30: 191–296.

    CAS  PubMed  Google Scholar 

  44. Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–784.

    CAS  PubMed  Google Scholar 

  45. Spange S, Wagner T, Heinzel T, Krämer OH . Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol 2009; 41: 185–198.

    CAS  PubMed  Google Scholar 

  46. Minucci S, Pelicci PG . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 2006; 6: 38–51.

    CAS  PubMed  Google Scholar 

  47. Müller S, Krämer OH . Inhibitors of HDACs—effective drugs against cancer? Curr Cancer Drug Targets 2010; 10: 210–228.

    PubMed  Google Scholar 

  48. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F et al. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 2005; 280: 26729–26734.

    CAS  PubMed  Google Scholar 

  49. Nishioka C, Ikezoe T, Yang J, Takeuchi S, Koeffler HP, Yokoyama A . MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res 2008; 32: 1382–1392.

    CAS  PubMed  Google Scholar 

  50. Krämer OH, Müller S, Buchwald M, Reichardt S, Heinzel T . Mechanism for ubiquitylation of the leukemia fusion proteins AML1-ETO and PML-RARalpha. FASEB J 2008; 22: 1369–1379.

    PubMed  Google Scholar 

  51. Krämer OH, Zhu P, Ostendorff HP, Golebiewski M, Tiefenbach J, Peters MA et al. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. EMBO J 2003; 22: 3411–3420.

    PubMed  PubMed Central  Google Scholar 

  52. Makki MS, Heinzel T, Englert C . TSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels. Nucleic Acids Res 2008; 36: 4067–4078.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Alao JP, Lam EW, Ali S, Buluwela L, Bordogna W, Lockey P et al. Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines. Clin Cancer Res 2004; 10: 8094–8104.

    CAS  PubMed  Google Scholar 

  54. Mahboobi S, Uecker A, Sellmer A, Cenac C, Hocher H, Pongratz H et al. Novel bis(1H-indol-2-yl)methanones as potent inhibitors of FLT3 and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 2006; 49: 3101–3115.

    CAS  PubMed  Google Scholar 

  55. Bursen A, Moritz S, Gaussmann A, Moritz S, Dingermann T, Marschalek R . Interaction of AF4 wild-type and AF4.MLL fusion protein with SIAH proteins: indication for t(4;11) pathobiology? Oncogene 2004; 23: 6237–6249.

    CAS  PubMed  Google Scholar 

  56. 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.

    CAS  PubMed  Google Scholar 

  57. Krämer OH, Knauer SK, Greiner G, Jandt E, Reichardt S, Gührs KH et al. A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev 2009; 23: 223–235.

    PubMed  PubMed Central  Google Scholar 

  58. Fanelli M, Fantozzi A, De Luca P, Caprodossi S, Matsuzawa S, Lazar MA et al. The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome. J Biol Chem 2004; 279: 5374–5379.

    CAS  PubMed  Google Scholar 

  59. Heidel F, Lipka DB, Mirea FK, Mahboobi S, Grundler R, Kancha RK et al. Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro. Br J Haematol 2009; 144: 865–874.

    CAS  PubMed  Google Scholar 

  60. Masson K, Ronnstrand L . Oncogenic signaling from the hematopoietic growth factor receptors c-Kit and Flt3. Cell Signal 2009; 21: 1717–1726.

    CAS  PubMed  Google Scholar 

  61. Krämer OH, Knauer SK, Zimmermann D, Stauber RH, Heinzel T . Histone deacetylase inhibitors and hydroxyurea modulate the cell cycle and cooperatively induce apoptosis. Oncogene 2008; 27: 732–740.

    PubMed  Google Scholar 

  62. Kawagoe R, Kawagoe H, Sano K . Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. Leuk Res 2002; 26: 495–502.

    CAS  PubMed  Google Scholar 

  63. Wheeler TC, Chin LS, Li Y, Roudabush FL, Li L . Regulation of synaptophysin degradation by mammalian homologues of seven in absentia. J Biol Chem 2002; 277: 10273–10282.

    CAS  PubMed  Google Scholar 

  64. Lee JT, Wheeler TC, Li L, Chin LS . Ubiquitination of alpha-synuclein by Siah-1 promotes alpha-synuclein aggregation and apoptotic cell death. Hum Mol Genet 2008; 17: 906–917.

    CAS  PubMed  Google Scholar 

  65. Umebayashi K, Stenmark H, Yoshimori T . Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation. Mol Biol Cell 2008; 19: 3454–3462.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Masson K, Heiss E, Band H, Ronnstrand L . Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. Biochem J 2006; 399: 59–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Jacob C, Cottrell GS, Gehringer D, Schmidlin F, Grady EF, Bunnett NW . c-Cbl mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2. J Biol Chem 2005; 280: 16076–16087.

    CAS  PubMed  Google Scholar 

  68. Miyake S, Lupher Jr ML, Druker B, Band H . The tyrosine kinase regulator Cbl enhances the ubiquitination and degradation of the platelet-derived growth factor receptor alpha. Proc Natl Acad Sci USA 1998; 95: 7927–7932.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Cho JY, Guo C, Torello M, Lunstrum GP, Iwata T, Deng C et al. Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia. Proc Natl Acad Sci USA 2004; 101: 609–614.

    CAS  PubMed  Google Scholar 

  70. Glaser KB . HDAC inhibitors: clinical update and mechanism-based potential. Biochem Pharmacol 2007; 74: 659–671.

    CAS  PubMed  Google Scholar 

  71. Kuendgen A, Gattermann N . Valproic acid for the treatment of myeloid malignancies. Cancer 2007; 110: 943–954.

    CAS  PubMed  Google Scholar 

  72. Lierman E, Lahortiga I, Van Miegroet H, Mentens N, Marynen P, Cools J . The ability of sorafenib to inhibit oncogenic PDGFRbeta and FLT3 mutants and overcome resistance to other small molecule inhibitors. Haematologica 2007; 92: 27–34.

    CAS  PubMed  Google Scholar 

  73. Kasper S, Breitenbuecher F, Hoehn Y, Heidel F, Lipka DB, Markova B et al. The kinase inhibitor LS104 induces apoptosis, enhances cytotoxic effects of chemotherapeutic drugs and is targeting the receptor tyrosine kinase FLT3 in acute myeloid leukemia. Leuk Res 2008; 32: 1698–1708.

    CAS  PubMed  Google Scholar 

  74. Kiyoi H, Shiotsu Y, Ozeki K, Yamaji S, Kosugi H, Umehara H et al. A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations. Clin Cancer Res 2007; 13 (15 Part 1): 4575–4582.

    CAS  PubMed  Google Scholar 

  75. Auclair D, Miller D, Yatsula V, Pickett W, Carter C, Chang Y et al. Antitumor activity of sorafenib in FLT3-driven leukemic cells. Leukemia 2007; 21: 439–445.

    CAS  PubMed  Google Scholar 

  76. Yokouchi M, Kondo T, Houghton A, Bartkiewicz M, Horne WC, Zhang H et al. Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7. J Biol Chem 1999; 274: 31707–31712.

    CAS  PubMed  Google Scholar 

  77. Levkowitz G, Waterman H, Ettenberg SA, Katz M, Tsygankov AY, Alroy I et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol Cell 1999; 4: 1029–1040.

    CAS  PubMed  Google Scholar 

  78. Padron D, Sato M, Shay JW, Gazdar AF, Minna JD, Roth MG . Epidermal growth factor receptors with tyrosine kinase domain mutations exhibit reduced Cbl association, poor ubiquitylation, and down-regulation but are efficiently internalized. Cancer Res 2007; 67: 7695–7702.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Yang S, Qu S, Perez-Tores M, Sawai A, Rosen N, Solit DB et al. Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors. Cancer Res 2006; 66: 6990–6997.

    CAS  PubMed  Google Scholar 

  80. Mak HH, Peschard P, Lin T, Naujokas MA, Zuo D, Park M . Oncogenic activation of the Met receptor tyrosine kinase fusion protein, Tpr-Met, involves exclusion from the endocytic degradative pathway. Oncogene 2007; 26: 7213–7221.

    CAS  PubMed  Google Scholar 

  81. Toffalini F, Kallin A, Vandenberghe P, Pierre P, Michaux L, Cools J et al. The fusion proteins TEL-PDGFRbeta and FIP1L1-PDGFRalpha escape ubiquitination and degradation. Haematologica 2009; 94: 1085–1093.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Reindl C, Quentmeier H, Petropoulos K, Greif PA, Benthaus T, Argiropoulos B et al. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res 2009; 15: 2238–2247.

    CAS  PubMed  Google Scholar 

  83. Zhou Q, Agoston AT, Atadja P, Nelson WG, Davidson NE . Inhibition of histone deacetylases promotes ubiquitin-dependent proteasomal degradation of DNA methyltransferase 1 in human breast cancer cells. Mol Cancer Res 2008; 6: 873–883.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Minami Y, Kiyoi H, Yamamoto Y, Yamamoto K, Ueda R, Saito H et al. Selective apoptosis of tandemly duplicated FLT3-transformed leukemia cells by Hsp90 inhibitors. Leukemia 2002; 16: 1535–1540.

    CAS  PubMed  Google Scholar 

  85. Beck R, Verrax J, Gonze T, Zappone M, Pedrosa RC, Taper H et al. Hsp90 cleavage by an oxidative stress leads to its client proteins degradation and cancer cell death. Biochem Pharmacol 2009; 77: 375–383.

    CAS  PubMed  Google Scholar 

  86. Gausdal G, Gjertsen BT, Fladmark KE, Demol H, Vandekerckhove J, Doskeland SO . Caspase-dependent, geldanamycin-enhanced cleavage of co-chaperone p23 in leukemic apoptosis. Leukemia 2004; 18: 1989–1996.

    CAS  PubMed  Google Scholar 

  87. Rao RV, Niazi K, Mollahan P, Mao X, Crippen D, Poksay KS et al. Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23. Cell Death Differ 2006; 13: 415–425.

    CAS  PubMed  Google Scholar 

  88. Deheuninck J, Goormachtigh G, Foveau B, Ji Z, Leroy C, Ancot F et al. Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage. Cell Signal 2009; 21: 1455–1463.

    CAS  PubMed  Google Scholar 

  89. Strohecker AM, Yehiely F, Chen F, Cryns VL . Caspase cleavage of HER-2 releases a Bad-like cell death effector. J Biol Chem 2008; 283: 18269–18282.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. He YY, Huang JL, Chignell CF . Cleavage of epidermal growth factor receptor by caspase during apoptosis is independent of its internalization. Oncogene 2006; 25: 1521–1531.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank R Marschalek for SIAH1 and SIAH2 plasmids, I Dikic for providing the CBL construct, S Knauer for help with immunocytochemistry, A Böhmer for helpful discussion, D Arora for quantitative mRNA expression analysis, and G Greiner and S Reichardt for excellent technical assistance. This work was in part supported by the Deutsche Forschungsgemeinschaft (SFB 604) to TH, Landesprogramm ‘ProExzellenz’ des Freistaates Thüringen (PE 123-2-1) to OHK and a grant of the Deutsche Krebshilfe (‘Ongogenic Networks in the Pathogenesis of AML’, no. 108401) to FDB.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to O H Krämer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buchwald, M., Pietschmann, K., Müller, J. et al. Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation. Leukemia 24, 1412–1421 (2010). https://doi.org/10.1038/leu.2010.114

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.114

Keywords

This article is cited by

Search

Quick links