Department of Physiological Chemistry I, Biocenter, University of Würzburg, Würzburg, Germany.
BMC Evol Biol. 2010 Jan 27;10:27. doi: 10.1186/1471-2148-10-27.
The epidermal growth factor receptor (Egfr) with its numerous ligands has fundamental roles in development, cell differentiation and physiology. Dysfunction of the receptor-ligand system contributes to many human malignancies. Consistent with such various tasks, the Egfr gene family has expanded during vertebrate evolution as a consequence of several rounds of whole genome duplication. Of particular interest is the effect of the fish-specific whole genome duplication (FSGD) on the ligand-receptor system, as it has supplied this largest group of vertebrates with additional opportunities for sub- and/or neofunctionalization in this signaling system.
We identified the predicted components of the Egf receptor-ligand signaling system in teleost fishes (medaka, platyfish, stickleback, pufferfishes and zebrafish). We found two duplicated egfr genes, egfra and egfrb, in all available teleost genomes. Surprisingly only one copy for each of the seven Egfr ligands could be identified in most fishes, with zebrafish hbegf being the only exception. Special focus was put on medaka, for which we more closely investigated all Egf receptors and Egfr ligands. The different expression patterns of egfra, egfrb and their ligands in medaka tissues and embryo stages suggest differences in role and function. Preferential co-expression of different subsets of Egfr ligands corroborates the possible subfunctionalization and specialization of the two receptors in adult tissues. Bioinformatic analyses of the ligand-receptor interface between Egfr and its ligands show a very weak evolutionary conservation within this region. Using in vitro analyses of medaka Egfra, we could show that this receptor is only activated by medaka ligands, but not by human EGF. Altogether, our data suggest a lineage-specific Egfr/Egfr ligand co-evolution.
Our data indicate that medaka Egfr signaling occurs via its two copies, Egfra and Egfrb, each of them being preferentially coexpressed with different subsets of Egfr ligands. This fish-specific occurrence of Egf receptor specialization offers unique opportunities to study the functions of different Egf receptor-ligand combinations and their biological outputs in vertebrates. Furthermore, our results strongly support the use of homologous ligands in future studies, as sufficient cross-specificity is very unlikely for this ligand/receptor system.
表皮生长因子受体（Egfr）及其众多配体在发育、细胞分化和生理学中起着重要作用。受体-配体系统的功能障碍导致许多人类恶性肿瘤的发生。与这些多样化的任务一致，Egfr 基因家族在脊椎动物进化过程中通过几次全基因组复制而扩张。特别有趣的是鱼类特异性全基因组复制（FSGD）对配体-受体系统的影响，因为它为这个最大的脊椎动物群体在这个信号系统中提供了更多的亚功能化和/或新功能化的机会。
我们在硬骨鱼类（日本青鳉、平鳍美洲蟾鱼、棘背鱼、河豚和斑马鱼）中鉴定了 Egf 受体-配体信号系统的预测成分。我们在所有可用的硬骨鱼类基因组中发现了两个复制的 egfr 基因，egfra 和 egfrb。令人惊讶的是，除了斑马鱼 hbegf 外，大多数鱼类只能鉴定到七种 Egfr 配体中的一种拷贝。我们特别关注日本青鳉，对其进行了更深入的研究，包括所有 Egf 受体和 Egfr 配体。在日本青鳉组织和胚胎阶段，egfra、egfrb 及其配体的不同表达模式表明它们在功能上存在差异。不同亚群的 Egfr 配体的优先共表达证实了这两个受体在成年组织中的亚功能化和专业化。对 Egfr 与其配体之间配体-受体界面的生物信息学分析表明，该区域的进化保守性非常弱。使用日本青鳉 Egfra 的体外分析，我们可以证明这种受体仅被日本青鳉配体激活，而不能被人 EGF 激活。总的来说，我们的数据表明了谱系特异性的 Egfr/Egfr 配体共同进化。
我们的数据表明，日本青鳉的 Egfr 信号转导通过其两个拷贝 Egfra 和 Egfrb 进行，每个拷贝都与不同亚群的 Egfr 配体优先共表达。这种鱼类特有的 Egf 受体专门化提供了独特的机会来研究不同的 Egf 受体-配体组合及其在脊椎动物中的生物学输出功能。此外，我们的结果强烈支持在未来的研究中使用同源配体，因为对于这个配体/受体系统来说，充分的交叉特异性是不太可能的。
