CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells
CIN85 is required for Cbl-mediated regulation of antigen receptor signaling in human B cells
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DOI：
10.1182/blood-2011-04-351965
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发表时间：
2012-03-08
期刊：
影响因子：
20.3
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
--
作者：
Niiro, Hiroaki;Jabbarzadeh-Tabrizi, Siamak;Akashi, Koichi
B细胞受体（BCR）信号传导的异常调节允许不需要的B细胞持续存在，从而潜在地导致自身免疫和B细胞恶性肿瘤。Casitas B系淋巴瘤（Cbl）蛋白抑制BCR信号传导;然而，控制人B细胞中Cbl功能的分子机制仍不清楚。在这里，我们证明，CIN 85（c-Cbl相互作用蛋白的85 kDa）是组成性相关的c-Cbl，Cbl-B，和B细胞接头在B细胞。使用CIN 85过表达和CIN 85敲低的B细胞系的实验显示，CIN 85增加c-Cbl磷酸化，抑制BCR诱导的钙流和Syk和PLC γ 2的磷酸化，而它不影响BCR内化。在CIN 85过表达和CIN 85敲低的细胞中，Syk的磷酸化与Syk的泛素化和降解呈负相关。此外，原代B细胞中的CIN 85敲低增强了BCR诱导的存活和生长，并增加了BcLxL、A1、细胞周期蛋白D2和myc的表达。在BCR和Toll样受体9的刺激下，B细胞分化相关分子在CIN 85敲低的细胞中上调。总之，这些结果表明，CIN 85是Cbl介导的BCR信号转导调节和下游事件如人B细胞的存活、生长和分化所必需的。（血。2012;119（10）：2263-2273）
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 PLC gamma 2, 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. (Blood. 2012;119(10): 2263-2273)