c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130

Yoshinori Tanaka, Nobuyuki Tanaka, Yasushi Saeki, Keiji Tanaka, Masaaki Murakami, Toshio Hirano, Naoto Ishii, Kazuo Sugamura

研究成果: Article査読

66 被引用数 (Scopus)


Interleukin 6 (IL-6), a pleiotropic cytokine, functions in cells through its interaction with its receptor complex, which consists of two ligand-binding α subunits and two signal-transducing subunits known as gp130. There is a wealth of studies on signals mediated by gp130, but its downregulation is less well understood. Here we found that IL-6 stimulation induced lysosome-dependent degradation of gp130, which correlated with an increase in the K63-linked polyubiquitination of gp130. The stimulation-dependent ubiquitination of gp130 was mediated by c-Cbl, an E3 ligase, which was recruited to gp130 in a tyrosine-phosphorylated SHP2-dependent manner. We also found that IL-6 induced a rapid translocation of gp130 from the cell surface to endosomal compartments. Furthermore, the vesicular sorting molecule Hrs contributed to the lysosomal degradation of gp130 by directly recognizing its ubiquitinated form. Deficiency of either Hrs or c-Cbl suppressed gp130 degradation, which leads to a prolonged and amplified IL-6 signal. Thus, our present report provides the first evidence for involvement of a c-Cbl/SHP2 complex in ubiquitination and lysosomal degradation of gp130 upon IL-6 stimulation. The lysosomal degradation of gp130 is critical for cessation of IL-6-mediated signaling.

ジャーナルMolecular and cellular biology
出版ステータスPublished - 2008 8

ASJC Scopus subject areas

  • 分子生物学
  • 細胞生物学


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