Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma.
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.
Takeuchi
Tamotsu
T
Department of Pathology, Kochi Medical School, Nankoku, Kochi, Japan 783-8505. takeutit@med.kochi-ms.ac.jp
Adachi
Yoshihiro
Y
Ohtsuki
Yuji
Y
D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism*; D008954:Models, Biological; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch; D011994:Recombinant Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014162:Transfection; D044767:Ubiquitin-Protein Ligases
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; D051880:Receptors, Notch; D011994:Recombinant Proteins; D000072056:Transcription Factor HES-1; D044767:Ubiquitin-Protein Ligases; C490504:JAG2 protein, human; C078493:HES1 protein, human; C478156:MIB2 protein, human