α- and γ-Protocadherins Negatively Regulate PYK2
α- and γ-Protocadherins Negatively Regulate PYK2
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DOI：
10.1074/jbc.m807417200
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发表时间：
2009-01-30
影响因子：
4.8
通讯作者：
Wang, Xiaozhong
中科院分区：
文献类型：
--
作者：
Chen, Jian;Lu, Yanyan;Wang, Xiaozhong
遗传学研究表明，γ-原钙粘素（PCDH-γ）是中枢神经系统神经元亚群的生存和突触连接所必需的。然而，PCDH-γ的细胞内信号传导机制知之甚少。在这里，我们表明，PCDH-γ结合两个酪氨酸激酶，PYK 2和粘着斑激酶（FAK），与PCDH-γ抑制激酶活性的相互作用。与此一致，PYK 2活性在Pcdh-γ缺陷神经元中异常上调。PYK 2过表达诱导鸡脊髓细胞凋亡因此，通过PCDH对PYK 2活性的负调节可能有助于神经元亚群的存活。令人惊讶的是，我们发现PCDH-α与PYK 2和FAK类似地相互作用，尽管含有不同的胞质结构域。在神经组织中，PCDH-γ与PCDH-α一起与PYK 2和/或FAK形成功能复合物。因此，对PCDH-γ和PCDH-α的共同细胞内效应物的鉴定表明，由Pcdh-α和Pcdh-γ基因簇产生的数十种原钙粘蛋白可以将不同的细胞外信号会聚到共同的细胞内途径中。
Genetic studies demonstrate that gamma-protocadherins (PCDH-gamma) are required for the survival and synaptic connectivity in neuronal subpopulations of the central nervous system. However, the intracellular signaling mechanisms for PCDH-gamma are poorly understood. Here, we show that PCDH-gamma binds two tyrosine kinases, PYK2 and focal adhesion kinase (FAK), and interaction with PCDH-gamma inhibits kinase activity. Consistent with this, PYK2 activity is abnormally up-regulated in the Pcdh-gamma-deficient neurons. Overexpression of PYK2 induces apoptosis in the chicken spinal cord. Thus, negative regulation of PYK2 activity by PCDH could contribute to the survival of subsets of neurons. Surprisingly, we found that PCDH-alpha interacts similarly with PYK2 and FAK despite containing a distinct cytoplasmic domain. In neural tissue, PCDH-gamma, together with PCDH-alpha, forms functional complexes with PYK2 and/or FAK. Therefore, the identification of common intracellular effectors for PCDH-gamma and PCDH-alpha suggests that dozens of protocadherins generated by Pcdh-alpha and Pcdh-gamma gene clusters can converge different extracellular signals into common intracellular pathways.