RRC ID 1510
Author Takeuchi T, Adachi Y, Ohtsuki Y.
Title Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma.
Journal Am J Pathol
Abstract Recent research has indicated that ligand-dependent activation of the Notch receptor in stromal cells plays a crucial role in the tumorigenesis of multiple myeloma. Ubiquitination of intracellular regions of Notch receptor and its ligands is important for Notch signal transduction. In vitro autoubiquitination analysis using recombinant proteins identified skeletrophin as a novel RING finger-dependent ubiquitin ligase. Skeletrophin bound the intracellular regions of the Notch ligand Jagged-2, but not to those of Delta-1, -3, -4, or Jagged-1. Skeletrophin, but not its RING-mutated form, ubiquitinized the intracellular region of Jagged-2. In malignant plasma cells from 23 of 40 multiple myeloma specimens, strong skeletrophin expression was observed, especially from patients with osteolytic bone lesions. Cytoplasmic localization, which may indicate Jagged-2 internalization, was found in many skeletrophin-positive myeloma cells. In contrast, skeletrophin was only weakly expressed in a few nonneoplasmic plasma cells in chronically inflamed tissues. Interestingly, exogenous expression of skeletrophin, but not the RING-mutated form, in Jagged-2-positive P3U1 myeloma cells induced Hes-1 (Hairy and Enhancer of Split homolog-1) gene expression in Notch receptor-positive bone marrow stromal cells through direct cell-cell contact. Thus, skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells, possibly activating Hes-1 on stromal cells through ligand-dependent Notch signaling.
Volume 166(6)
Pages 1817-26
Published 2005-6-1
DOI 10.1016/S0002-9440(10)62491-1
PII S0002-9440(10)62491-1
PMID 15920166
PMC PMC1602431
MeSH Basic Helix-Loop-Helix Transcription Factors Blotting, Western Bone Marrow Cells / metabolism Cells, Cultured Coculture Techniques Gene Expression Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Humans Immunohistochemistry Intercellular Signaling Peptides and Proteins Jagged-2 Protein Membrane Proteins / metabolism Microfilament Proteins / metabolism* Models, Biological* Multiple Myeloma / metabolism* Multiple Myeloma / pathology* Neoplasm Proteins / metabolism* Polymerase Chain Reaction Receptors, Notch Recombinant Proteins / metabolism* Reverse Transcriptase Polymerase Chain Reaction Stromal Cells / metabolism Transcription Factor HES-1 Transfection Ubiquitin-Protein Ligases
IF 3.491
Times Cited 45
Human and Animal Cells ST2(RCB0224)