Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization
Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization
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DOI：
10.1074/jbc.m117.778399
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发表时间：
2018-02-09
影响因子：
4.8
通讯作者：
Okada-Hatakeyama, Mariko
中科院分区：
文献类型：
--
作者：
Magi, Shigeyuki;Iwamoto, Kazunari;Okada-Hatakeyama, Mariko
反馈控制是信号转导中的关键机制，密切参与调节细胞反应的结果。在这里，我们报告了一种新的机制，PHLDA 1，Pleckstrin同源样结构域，家庭A，成员1，负调控ErbB受体信号通过抑制受体寡聚化。我们已经发现ErbB 3配体heregulin诱导MCF-7细胞中PHILDA 1的表达。转录诱导的PHLDA 1蛋白直接与ErbB 3结合，而PHLDA 1的敲低增加ErbB 3和ErbB 2之间的复合物形成。为了深入了解我们的时间过程和单细胞实验观察的机制，我们进行了系统的计算搜索的网络拓扑结构的数学模型的基础上受体二聚体-四聚体形成的ErbB激活过程。我们的研究结果表明，只有一个模型，其中PHLDA 1抑制形成的二聚体和四聚体可以解释实验数据。通过单分子成像实验进一步验证了该模型的预测。我们的研究表明PHLDA 1具有独特的调节功能，可以抑制ErbB受体的寡聚化过程，从而控制受体信号网络的活性。
Feedback control is a key mechanism in signal transduction, intimately involved in regulating the outcome of the cellular response. Here, we report a novel mechanism by which PHLDA1, Pleckstrin homology-like domain, family A, member 1, negatively regulates ErbB receptor signaling by inhibition of receptor oligomerization. We have found that the ErbB3 ligand, heregulin, induces PHILDA1 expression in MCF-7 cells. Transcriptionally-induced PHLDA1 protein directly binds to ErbB3, whereas knockdown of PHLDA1 increases complex formation between ErbB3 and ErbB2. To provide insight into the mechanism for our time-course and single-cell experimental observations, we performed a systematic computational search of network topologies of the mathematical models based on receptor dimer-tetramer formation in the ErbB activation processes. Our results indicate that only a model in which PHLDA1 inhibits formation of both dimers and tetramer can explain the experimental data. Predictions made from this model were further validated by single-molecule imaging experiments. Our studies suggest a unique regulatory feature of PHLDA1 to inhibit the ErbB receptor oligomerization process and thereby control the activity of receptor signaling network.