Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor.
Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor.
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DOI：
10.1038/ncomms12038
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发表时间：
2016-06-30
影响因子：
16.6
通讯作者：
Epstein JA
中科院分区：
文献类型：
--
作者：
Aghajanian H;Cho YK;Manderfield LJ;Herling MR;Gupta M;Ho VC;Li L;Degenhardt K;Aharonov A;Tzahor E;Epstein JA
器官发生和再生需要细胞增殖的协调，部分由分泌的生长因子和同源受体调节，组织营养供应由血管的扩张和图案化提供。在这里，我们揭示了一个生长因子共受体与异二聚体的合作伙伴和配体已知的调节血管生成和血管图案意想不到的组合整合。我们发现，ErbB2，它可以介导表皮生长因子（EGF）和神经调节蛋白信号在多种组织中，意外地表达的内皮细胞，它与神经纤毛蛋白1（Nrp1）的合作伙伴，形成一个功能性受体的血管导向分子semaphorin 3d（Sema3d）。Sema3d的缺失导致冠状静脉的不适当图案化，这是由ErbB2的内皮缺失概括的表型。这些发现对通常用于癌症的抗ErbB2疗法的可能的心血管副作用具有影响，并提供了在组织生长和血管模式中涉及的途径的分子水平上整合的例子。 脑信号蛋白配体和同源受体在脉管系统的模式化中是重要的。在这里，Aghajanian等人报道了ErbB2在内皮细胞中的一个意想不到的作用，它与Nrp1合作形成胚胎血管图案所需的一种新的信号传递全受体。
Organogenesis and regeneration require coordination of cellular proliferation, regulated in part by secreted growth factors and cognate receptors, with tissue nutrient supply provided by expansion and patterning of blood vessels. Here we reveal unexpected combinatorial integration of a growth factor co-receptor with a heterodimeric partner and ligand known to regulate angiogenesis and vascular patterning. We show that ErbB2, which can mediate epidermal growth factor (EGF) and neuregulin signalling in multiple tissues, is unexpectedly expressed by endothelial cells where it partners with neuropilin 1 (Nrp1) to form a functional receptor for the vascular guidance molecule semaphorin 3d (Sema3d). Loss of Sema3d leads to improper patterning of the coronary veins, a phenotype recapitulated by endothelial loss of ErbB2. These findings have implications for possible cardiovascular side-effects of anti-ErbB2 therapies commonly used for cancer, and provide an example of integration at the molecular level of pathways involved in tissue growth and vascular patterning. Semaphorin ligands and cognate receptors are important in patterning the vasculature. Here, Aghajanian et al. report an unexpected role for ErbB2 in endothelial cells where it partners with Nrp1 to form a novel semaphoring holoreceptor required for embryonic vascular patterning.