Orchestration of ErbB3 signaling through heterointeractions and homointeractions.
Orchestration of ErbB3 signaling through heterointeractions and homointeractions.
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DOI：
10.1091/mbc.e14-06-1114
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发表时间：
2015-11-05
影响因子：
3.3
通讯作者：
Wilson BS
中科院分区：
文献类型：
--
作者：
McCabe Pryor M;Steinkamp MP;Halasz AM;Chen Y;Yang S;Smith MS;Zahoransky-Kohalmi G;Swift M;Xu XP;Hanein D;Volkmann N;Lidke DS;Edwards JS;Wilson BS
ErbB受体在家族成员之间形成同源二聚体和异源二聚体。为了对ErbB2/ErbB3信号进行建模，使用单粒子跟踪数据来创建具有重叠受体结构域的模拟空间。受体二聚化和磷酸化的随机模型揭示了ErbB2-3相互作用的复杂性。ErbB受体酪氨酸激酶家族成员既有同源相互作用，也有异源相互作用。由于每个受体都有一组独特的下游信号伙伴结合位点和不同的催化活性，它们组合相互作用中的细微变化可能会对信号转导结果产生很大影响。ErbB家族成员的过度表达和突变在许多人类癌症中很常见，并改变了信号网络中的激活平衡。在这里，我们报道了一个空间随机模型的发展，该模型用ErbB2研究ErbB3的同二聚化和异二聚化的动力学。该模型基于扩散、二聚体去化率、激酶活性和去磷酸化的实验测量。我们还报告了对ErbB3突变的计算分析，产生了这样的预测，即激活细胞内和细胞外域的突变可能被细分为具有不同潜在机制的类别。我们展示了位于C叶不对称二聚界面的ErbB3功能点获得突变的实验证据，这表明低配体剂量时磷酸化增强与激酶活性增加相关。
ErbB receptors form homodimers and heterodimers between family members. To model ErbB2/ErbB3 signaling, single-particle tracking data are used to create a simulation space with overlapping receptor domains. Stochastic modeling of receptor dimerization and phosphorylation reveals the complexity of ErbB2-3 interactions. Members of the ErbB family of receptor tyrosine kinases are capable of both homointeractions and heterointeractions. Because each receptor has a unique set of binding sites for downstream signaling partners and differential catalytic activity, subtle shifts in their combinatorial interplay may have a large effect on signaling outcomes. The overexpression and mutation of ErbB family members are common in numerous human cancers and shift the balance of activation within the signaling network. Here we report the development of a spatial stochastic model that addresses the dynamics of ErbB3 homodimerization and heterodimerization with ErbB2. The model is based on experimental measures for diffusion, dimer off-rates, kinase activity, and dephosphorylation. We also report computational analysis of ErbB3 mutations, generating the prediction that activating mutations in the intracellular and extracellular domains may be subdivided into classes with distinct underlying mechanisms. We show experimental evidence for an ErbB3 gain-of-function point mutation located in the C-lobe asymmetric dimerization interface, which shows enhanced phosphorylation at low ligand dose associated with increased kinase activity.