Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner
Src-like adaptor protein (SLAP) regulates B cell receptor levels in a c-Cbl-dependent manner
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DOI：
10.1073/pnas.0608965103
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发表时间：
2006-11-28
影响因子：
11.1
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
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作者：
Dragone, Leonard L.;Myers, Margaret D.;Weiss, Arthur
Src样衔接蛋白（Src-like adaptor protein，Src）和c-Cbl在调节T细胞受体（TCR）水平方面具有协同作用。SHBG也在发育中的B细胞中表达，其缺乏导致B细胞受体（BCR）水平和B细胞发育的改变。因此，我们推测，在B细胞发育过程中，SbR和c-Cbl可能协同调节BCR水平。我们发现，在同时缺乏SHBG和c-Cbl的小鼠中，B细胞的发育发生了改变，这表明它们通过交叉途径发挥作用。为了研究SbR和c-Cbl改变BCR水平的机制，我们在成熟小鼠B细胞系（Bal-17）中共表达了它们。首先，我们确定了在刺激和内化后，SSCP与BCR复合物的近端成分相关。在Bal-17中，Scr和c-Cb 1的共表达导致表面和总BCR水平降低。这种BCR水平的降低依赖于完整的Src同源性2（5142）和Src的C-末端结构域。此外，在SH 2结构域的突变的SHELL阻断其与c-Cbl和BCR复合物的共定位，而C末端的缺失并不影响其定位。最后，共同表达的SbR和c-Cbl改变BCR复合物回收。这种BCR复合物再循环的改变依赖于具有酶活性的c-Cbl和Src家族激酶，以及完整的SH 2和S-末端结构域。这些数据表明，通过使c-Cbl适应抗原-受体复合物并靶向其降解，Scr在B和T细胞中具有保守的功能。
Src-like adaptor protein (SLAP) and c-Cbl recently have been shown to cooperate in regulating T cell receptor (TCR) levels in developing T cells. SLAP also is expressed in developing B cells, and its deficiency leads to alterations in B cell receptor (BCR) levels and B cell development. Hence, we hypothesized that SLAP and c-Cbl may cooperate during B cell development to regulate BCR levels. In mice deficient in both SLAP and c-Cbl, we found that B cell development is altered, suggesting that they function through intersecting pathways. To study the mechanism by which SLAP and c-Cbl alter BCR levels, we coexpressed them in a mature mouse B cell line (Bal-17). First we determined that SLAP associates with proximal components of the BCR complex after stimulation and internalization. Coexpression of SLAP and c-Cb1 in Bal-17 led to decreased surface and total BCR levels. This decrease in BCR levels depended on intact Src homology 2 (5142) and C-terminal domains of SLAP. In addition, a mutation in the SH2 domain of SLAP blocked its colocalization with c-Cbl and the BCR complex, whereas deletion of the C terminus did not affect its localization. Last, coexpression of SLAP and c-Cbl altered BCR complex recycling. This alteration in BCR complex recycling depended on enzymatically active c-Cbl and Src family kinases, as well as the intact SH2 and C-terminal domains of SLAP. These data suggest that SLAP has a conserved function in B and T cells by adapting c-Cbl to the a ntigen-receptor complex and targeting it for degradation.