CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells |
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Authors: | Niiro Hiroaki Jabbarzadeh-Tabrizi Siamak Kikushige Yoshikane Shima Takahiro Noda Kumiko Ota Shun-Ichiro Tsuzuki Hirofumi Inoue Yasushi Arinobu Yojiro Iwasaki Hiromi Shimoda Shinji Baba Eishi Tsukamoto Hiroshi Horiuchi Takahiko Taniyama Tadayoshi Akashi Koichi |
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Institution: | Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. hniiro@med.kyushu-u.ac.jp |
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Abstract: | 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. |
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