Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene
Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene
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DOI：
10.1038/sj.mp.4001991
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发表时间：
2008-02-01
影响因子：
11
通讯作者：
O'Donovan, M. C.
中科院分区：
文献类型：
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作者：
Buxbaum, J. D.;Georgieva, L.;O'Donovan, M. C.
神经调节蛋白和神经调节蛋白受体ERBB4在遗传和功能上与精神分裂症有关。在这项研究中，我们使用酵母双杂交系统来鉴定与ERBB4相互作用的蛋白质，以鉴定可能导致精神分裂症易感性的基因和途径。我们将MAGI支架蛋白鉴定为erbb4结合蛋白。在哺乳动物细胞中验证了MAGI蛋白与ERBB4的相互作用后，我们证明了ERBB4的表达，无论是单独表达还是与ERBB2或ERBB3联合表达，都会导致MAGI蛋白的酪氨酸磷酸化，并且这种磷酸化可以通过神经调节蛋白的受体激活进一步增强。由于MAGI蛋白先前被证明与受体磷酸酪氨酸磷酸酶β / ζ (RPTP β)相互作用，我们假设MAGI蛋白与RPTP β和ERBB4同时结合形成磷酸酪氨酸激酶/磷酸酪氨酸磷酸酶复合物。在培养细胞中的研究证实了ERBB4、MAGI和RPTP β之间的空间和功能关联。鉴于这种功能关联的证据，我们在英国高加索病例对照队列（n=约1400）中检测了MAGI和RPTP β编码基因与精神分裂症的遗传关联。在我们的研究中，编码RPTP β的PTPRZ1与精神分裂症表现出显著的基因范围和假设范围的相关性（最佳个体单核苷酸多态性等位基因P = 0.0003；基因范围P = 0.0064；假设范围P = 0.026）。这些数据为PTPRZ1和RPTP β信号异常在精神分裂症病因学中的作用提供了证据。此外，这些数据表明RPTP β在ERBB4信号的调节中发挥作用，这可能反过来进一步支持神经调节蛋白/ERBB4信号在精神分裂症分子基础中的重要作用。
Neuregulin and the neuregulin receptor ERBB4 have been genetically and functionally implicated in schizophrenia. In this study, we used the yeast two-hybrid system to identify proteins that interact with ERBB4, to identify genes and pathways that might contribute to schizophrenia susceptibility. We identified the MAGI scaffolding proteins as ERBB4-binding proteins. After validating the interaction of MAGI proteins with ERBB4 in mammalian cells, we demonstrated that ERBB4 expression, alone or in combination with ERBB2 or ERBB3, led to the tyrosine phosphorylation of MAGI proteins, and that this could be further enhanced with receptor activation by neuregulin. As MAGI proteins were previously shown to interact with receptor phosphotyrosine phosphatase beta/zeta(RPTP beta), we postulated that simultaneous binding of MAGI proteins to RPTP beta and ERBB4 forms a phosphotyrosine kinase/phosphotyrosine phosphatase complex. Studies in cultured cells confirmed both a spatial and functional association between ERBB4, MAGI and RPTP beta. Given the evidence for this functional association, we examined the genes coding for MAGI and RPTP beta for genetic association with schizophrenia in a Caucasian United Kingdom case-control cohort (n= similar to 1400). PTPRZ1, which codes for RPTP beta, showed significant, gene-wide and hypothesis-wide association with schizophrenia in our study (best individual single-nucleotide polymorphism allelic P = 0.0003; gene-wide P = 0.0064; hypothesis-wide P = 0.026). The data provide evidence for a role of PTPRZ1, and for RPTP beta signaling abnormalities, in the etiology of schizophrenia. Furthermore, the data indicate a role for RPTP beta in the modulation of ERBB4 signaling that may in turn provide further support for an important role of neuregulin/ERBB4 signaling in the molecular basis of schizophrenia.