Identification and characterization of EBP, a novel EEN binding protein that inhibits Ras signaling and is recruited into the nucleus by the MLL-EEN fusion protein.
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.
Yam
Judy Wai Ping
JW
Department of Pathology, University of Hong Kong.
Jin
Dong-Yan
DY
So
Chi Wai
CW
Chan
Li Chong
LC
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D055232:Proline-Rich Protein Domains; D011485:Protein Binding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011519:Proto-Oncogenes; D015398:Signal Transduction / Q000502:physiology; D020664:Son of Sevenless Proteins / Q000378:metabolism; D013251:Steroid Isomerases; D014157:Transcription Factors; D014178:Translocation, Genetic; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins / Q000378:metabolism*
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C482572:MLL-EEN fusion protein, human; D029543:Nucleocytoplasmic Transport Proteins; D015514:Oncogene Proteins, Fusion; D010455:Peptides; D011506:Proteins; D011518:Proto-Oncogene Proteins; C105159:SH3GL1 protein, human; C485509:SOS2 protein, human; D020664:Son of Sevenless Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D018631:ras Proteins; C490380:Ebp protein, mouse; D013251:Steroid Isomerases; C090445:EBP protein, human