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

Blood. 2004 Feb 15;103(4):1445-53. doi: 10.1182/blood-2003-07-2452. Epub 2003 Oct 9.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Carrier Proteins / chemistry
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Molecular Sequence Data
  • Myeloid-Lymphoid Leukemia Protein
  • Nucleocytoplasmic Transport Proteins*
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / metabolism
  • Peptides / genetics
  • Peptides / metabolism
  • Proline-Rich Protein Domains
  • Protein Binding
  • Proteins / genetics*
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogenes*
  • Signal Transduction / physiology
  • Son of Sevenless Proteins / metabolism
  • Steroid Isomerases*
  • Transcription Factors*
  • Translocation, Genetic
  • ets-Domain Protein Elk-1
  • ras Proteins / metabolism*

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • ELK1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • KMT2A protein, human
  • MLL-EEN fusion protein, human
  • Nucleocytoplasmic Transport Proteins
  • Oncogene Proteins, Fusion
  • Peptides
  • Proteins
  • Proto-Oncogene Proteins
  • SH3GL1 protein, human
  • SOS2 protein, human
  • Son of Sevenless Proteins
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • ras Proteins
  • Ebp protein, mouse
  • Steroid Isomerases
  • EBP protein, human