Abstract
The chimeric MLL-EEN fusion protein is created as a result of chromosomal translocation t(11;19)(q23;p13). EEN, an Src homology 3 (SH3) domain-containing protein in the endophilin family, has been implicated in endocytosis, although little is known about its role in leukemogenesis mediated by the MLL-EEN fusion protein. In this study, we have identified and characterized EBP, a novel EEN binding protein that interacts with the SH3 domain of EEN through a proline-rich motif PPERP. EBP is a ubiquitous protein that is normally expressed in the cytoplasm but is recruited to the nucleus by MLL-EEN with a punctate localization pattern characteristic of the MLL chimeric proteins. EBP interacts simultaneously with EEN and Sos, a guanine-nucleotide exchange factor for Ras. Coexpressoin of EBP with EEN leads to suppression of Ras-induced cellular transformation and Ras-mediated activation of Elk-1. Taken together, our findings suggest a new mechanism for MLL-EEN-mediated leukemogenesis in which MLL-EEN interferes with the Ras-suppressing activities of EBP through direct interaction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Carrier Proteins / chemistry
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Nucleus / metabolism
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Cell Transformation, Neoplastic
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Cytoplasm / metabolism
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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HeLa Cells
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Histone-Lysine N-Methyltransferase
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Humans
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Intracellular Signaling Peptides and Proteins
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Molecular Sequence Data
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Myeloid-Lymphoid Leukemia Protein
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Nucleocytoplasmic Transport Proteins*
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Peptides / genetics
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Peptides / metabolism
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Proline-Rich Protein Domains
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Protein Binding
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Proteins / genetics*
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogenes*
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Signal Transduction / physiology
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Son of Sevenless Proteins / metabolism
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Steroid Isomerases*
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Transcription Factors*
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Translocation, Genetic
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ets-Domain Protein Elk-1
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ras Proteins / metabolism*
Substances
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Carrier Proteins
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DNA-Binding Proteins
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ELK1 protein, human
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Intracellular Signaling Peptides and Proteins
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KMT2A protein, human
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MLL-EEN fusion protein, human
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Nucleocytoplasmic Transport Proteins
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Oncogene Proteins, Fusion
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Peptides
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Proteins
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Proto-Oncogene Proteins
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SH3GL1 protein, human
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SOS2 protein, human
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Son of Sevenless Proteins
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Transcription Factors
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ets-Domain Protein Elk-1
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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ras Proteins
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Ebp protein, mouse
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Steroid Isomerases
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EBP protein, human