TY - JOUR
T1 - Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma
AU - Takeuchi, Tamotsu
AU - Adachi, Yoshihiro
AU - Ohtsuki, Yuji
N1 - Funding Information:
Supported by the Ministry of Education of Japan (grants KAKEN12670165, 13670177 ), the Medical Research Fund of the Kochi Medical School, and the Vice-Chancellor of the Kochi Medical School (project grant for overseas study).
PY - 2005/6
Y1 - 2005/6
N2 - 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.
AB - 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.
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U2 - 10.1016/S0002-9440(10)62491-1
DO - 10.1016/S0002-9440(10)62491-1
M3 - Article
C2 - 15920166
AN - SCOPUS:18544373198
VL - 166
SP - 1817
EP - 1826
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -