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

Research output: Contribution to journalArticlepeer-review

15 Citations (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.

Original languageEnglish
Pages (from-to)2263-2273
Number of pages11
Issue number10
Publication statusPublished - Mar 8 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


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