CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells

Hiroaki Niiro, Siamak Jabbarzadeh-Tabrizi, Yoshikane Kikushige, Takahiro Shima, Kumiko Noda, Shun Ichiro Ota, Hirofumi Tsuzuki, Yasushi Inoue, Yojiro Arinobu, Hiromi Iwasaki, Shinji Shimoda, Eishi Baba, Hiroshi Tsukamoto, Takahiko Horiuchi, Tadayoshi Taniyama, Koichi Akashi

研究成果: ジャーナルへの寄稿学術誌査読

15 被引用数 (Scopus)


The aberrant regulation of B-cell receptor (BCR) signaling allows unwanted B cells to persist, thereby potentially leading to autoimmunity and B-cell malignancies. Casitas B-lineage lymphoma (Cbl) proteins suppress BCR signaling; however, the molecular mechanisms that control Cbl function in human B cells remain unclear. Here, we demonstrate that CIN85 (c-Cbl interacting protein of 85 kDa) is constitutively associated with c-Cbl, Cbl-b, and B-cell linker in B cells. Experiments using CIN85-overexpressing and CIN85-knockdown B-cell lines revealed that CIN85 increased c-Cbl phosphorylation and inhibited BCR-induced calcium flux and phosphorylation of Syk and PLCγ2, whereas it did not affect BCR internalization. The Syk phosphorylation in CIN85-overexpressing and CIN85-knockdown cells was inversely correlated with the ubiquitination and degradation of Syk. Moreover, CIN85 knockdown in primary B cells enhanced BCR-induced survival and growth, and increased the expression of BcLxL, A1, cyclin D2, and myc. Following the stimulation of BCR and Toll-like receptor 9, B-cell differentiation-associated molecules were up-regulated in CIN85-knockdown cells. Together, these results suggest that CIN85 is required for Cbl-mediated regulation of BCR signaling and for downstream events such as survival, growth, and differentiation of human B cells.

出版ステータス出版済み - 3月 8 2012

!!!All Science Journal Classification (ASJC) codes

  • 生化学
  • 免疫学
  • 血液学
  • 細胞生物学


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