The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation
The adaptor protein CIN85 assembles intracellular signaling clusters for B cell activation
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DOI：
10.1126/scisignal.aad6275
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发表时间：
2016-06-28
影响因子：
7.3
通讯作者：
Wienands, Juergen
中科院分区：
文献类型：
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作者：
Kuehn, Julius;Wong, Leo E.;Wienands, Juergen
85 kD 的接头分子 Cbl 相互作用蛋白 (CIN85) 调节来自许多细胞表面受体的信号传导，例如淋巴细胞上的生长因子受体和抗原受体。由于其多结构域结构，CIN85 被认为是一种经典的衔接蛋白，可通过不同的蛋白结构域连接给定信号通路的功能上不同的组件。然而，我们发现在 B 淋巴细胞中，CIN85 的功能是寡聚化 SLP-65，SLP-65 是 B 细胞受体 (BCR) 的中心效应蛋白。因此，CIN85 通过羧基末端卷曲螺旋结构域三聚化。三聚体 CIN85 分子的多个 Src 同源 3 (SH3) 结构域与多个 SLP-65 分子相关，从而招募更多的 CIN85 三聚体，从而使寡聚化过程永久化。这种寡聚信号复合物在静息 B 细胞中的形成使细胞做好了在 BCR 刺激后有效启动细胞内信号传导的准备。我们的数据表明，信号级联的功能不仅仅依赖于其各个组件的定性联系，而是需要临界数量的效应器集中在信号复合物中。
The adaptor molecule Cbl-interacting protein of 85 kD (CIN85) regulates signaling from a number of cell surface receptors, such as growth factor receptors and antigen receptors on lymphocytes. Because of its multidomain structure, CIN85 is thought to act as a classical adaptor protein that connects functionally distinct components of a given signaling pathway through diverse protein domains. However, we found that in B lymphocytes, CIN85 functions to oligomerize SLP-65, which is the central effector protein of the B cell receptor (BCR). Therefore, CIN85 trimerizes through a carboxyl-terminal, coiled-coil domain. The multiple Src homology 3 (SH3) domains of trimeric CIN85 molecules associated with multiple SLP- 65 molecules, which recruited further CIN85 trimers, thereby perpetuating the oligomerization process. Formation of this oligomeric signaling complex in resting B cells rendered the cells poised for the efficient initiation of intracellular signaling upon BCR stimulation. Our data suggest that the functionality of signaling cascades does not rely solely on the qualitative linkage of their various components but requires a critical number of effectors to become concentrated in signaling complexes.