ArticleThe Journal of biological chemistry2011
c-Cbl and Cbl-b ligases mediate 17-allylaminodemethoxygeldanamycin-induced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 45 citations in OpenAlex.
- Complexes Formed by the K63-Specific Deubiquitinating Enzyme BRCC36: New Promising Therapeutic Targets in Human Disease.Biomolecules · 2025Review
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- Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.The Journal of clinical investigation · 2024Article
- Targeting USP14/UCHL5: A Breakthrough Approach to Overcoming Treatment-Resistant FLT3-ITD-Positive AML.International journal of molecular sciences · 2024Article
- Importance of PTM of FLT3 in acute myeloid leukemia.Acta biochimica et biophysica Sinica · 2024Review
- BRCC36 associates with FLT3-ITD to regulate its protein stability and intracellular signaling in acute myeloid leukemia.Cancer science · 2024Article
- Article
- Small Molecule Induced FLT3 Degradation.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches.OncoTargets and therapy · 2022Review
- Article
- Arsenic trioxide induces autophagic degradation of the FLT3-ITD mutated protein in FLT3-ITD acute myeloid leukemia cells.Journal of Cancer · 2020Article
- Article
- Inhibition of the STAT5/Pim Kinase Axis Enhances Cytotoxic Effects of Proteasome Inhibitors on FLT3-ITD-Positive AML Cells by Cooperatively Inhibiting the mTORC1/4EBP1/S6K/Mcl-1 Pathway.Translational oncology · 2019Article
- Heat shock protein 90 inhibitors overcome the resistance to Fms-like tyrosine kinase 3 inhibitors in acute myeloid leukemia.Oncotarget · 2018Article
- ETV6/FLT3 Fusion Is a Novel Client Protein of Hsp90.Oncology research · 2018Article
- Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.Oncotarget · 2018Article
- Article
- Akt regulates neurite growth by phosphorylation-dependent inhibition of radixin proteasomal degradation.Scientific reports · 2018Article
- Article
- Molecular mechanisms for enhancement of stromal cell-derived factor 1-induced chemotaxis by platelet endothelial cell adhesion molecule 1 (PECAM-1).The Journal of biological chemistry · 2017Article
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5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The class III receptor-tyrosine kinase Flt3 regulates normal hematopoiesis. An internal tandem duplication (ITD) in the juxtamembrane domain of Flt3 (Flt3-ITD) contributes to transformation and is associated with poor prognosis in acute myeloid leukemia. Here, we demonstrate that, as compared with wild-type Flt3 (Flt3-WT), Flt3-ITD more rapidly undergoes degradation through the proteasomal and lysosomal pathways in model hematopoietic 32D cells and in human leukemic MV4-11 cells. The Hsp90 inhibitor 17-allylaminodemethoxygeldanamycin (17-AAG) preferentially induced the polyubiquitination and proteasomal degradation of Flt3-ITD autophosphorylated on Tyr-591 in these cells. The E3 ubiquitin ligases c-Cbl and to a lesser extent Cbl-b facilitated at least partly Lys-48-linked polyubiquitination of autophosphorylated Flt3-ITD when coexpressed in 293T cells. Moreover, c-Cbl and Cbl-b facilitated degradation of Flt3-ITD in 293T cells and significantly enhanced the 17-AAG-induced decline in autophosphorylated Flt3-ITD. The enhancement of Flt3-ITD degradation was also observed in 32D cells inducibly overexpressing c-Cbl or Cbl-b. Furthermore, overexpression of loss-of-function mutants of both c-Cbl (c-Cbl-R420Q) and Cbl-b (Cbl-b-C373A) together in 32D cells retarded the degradation of autophosphorylated Flt3-ITD and significantly inhibited the 17-AAG-induced degradation of Flt3-ITD to confer the resistance to cytotoxicity of 17-AAG on these cells. These results suggest that c-Cbl as well as Cbl-b may play important roles in Hsp90 inhibitor-induced degradation of Flt3-ITD through the ubiquitin proteasome system and in regulation of the basal expression level of Flt3-ITD in leukemic cells.
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