The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis.
The mixed lineage leukaemia gene, MLL (also called HRX, ALL-1) in acute leukaemia is fused to at least 16 identified partner genes that display diverse structural and biochemical properties. Using GST pull down and the yeast two hybrid system, we show that two different MLL fusion partners with SH3 domains, EEN and Abi-1, interact with dynamin and synaptojanin, both of which are involved in endocytosis. Synaptojanin, a member of the inositol phosphatase family that has recently been shown to regulate cell proliferation and survival, is also known to bind to Eps15, the mouse homologue of AF1p, another fusion partner of MLL. Expression studies show that synaptojanin is strongly expressed in bone marrow and immature leukaemic cell lines, very weakly in peripheral blood leukocytes and absent in Raji, a mature B cell line. We found that the SH3 domains of EEN and Abi-1 interact with different proline-rich domains of synaptojanin while the EH domains of Eps15 interact with the NPF motifs of synaptojanin. In vitro competitive binding assays demonstrate that EEN displays stronger binding affinity than Abi-1 and may compete with it for synaptojanin. These findings suggest a potential link between MLL fusion-mediated leukaemogenesis and the inositol-signalling pathway.
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Department of Pathology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, China.
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Cheung
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Chew
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Sham
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Chan
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D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D001667:Binding, Competitive; D001773:Blood Cells / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000235:genetics*; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D020869:Gene Expression Profiling; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007938:Leukemia / Q000209:etiology* / Q000235:genetics; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D005810:Multigene Family; D051788:Myeloid-Lymphoid Leukemia Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D009928:Organ Specificity; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D014178:Translocation, Genetic; D020798:Two-Hybrid System Techniques; D018909:src Homology Domains
C513733:ABI1 protein, human; C513734:Abi1 protein, mouse; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C105159:SH3GL1 protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases; D020558:GTP Phosphohydrolases; D034281:Dynamins