Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, India.
Gene. 2011 Aug 15;482(1-2):43-50. doi: 10.1016/j.gene.2011.05.007. Epub 2011 May 24.
The epidermal growth factor-Cripto-1/FRL-1/Cryptic (EGF-CFC) proteins, characterized by the highly conserved EGF and CFC domains, are extracellular membrane associated growth factor-like glycoproteins. These proteins are essential components of the Nodal signaling pathway during early vertebrate embryogenesis. Homologs of the EGF-CFC family have also been implicated in tumorigenesis in humans. Yet, little is known about the mode of molecular evolution in this family. Here we investigate the origin, extent of conservation and evolutionary relationships of EGF-CFC proteins across the metazoa. The results suggest that the first appearance of the EGF-CFC gene occurred in the ancestor of the deuterostomes. Phylogenetic analysis supports the classification of the family into distinct subfamilies that appear to have evolved through lineage-specific duplication and divergence. Site-specific analyses of evolutionary rate shifts between the two major mammalian paralogous subfamilies, Cripto and Cryptic, reveal critical amino acid sites that may account for the observed functional divergence. Furthermore, estimates of functional divergence suggest that rapid change of evolutionary rates at sites located mainly in the CFC domain may contribute towards distinct functional properties of the two paralogs.
表皮生长因子-Cripto-1/FRL-1/隐匿（EGF-CFC）蛋白，以高度保守的 EGF 和 CFC 结构域为特征，是细胞外膜相关的生长因子样糖蛋白。这些蛋白质是早期脊椎动物胚胎发生过程中 Nodal 信号通路的重要组成部分。EGF-CFC 家族的同源物也与人类肿瘤发生有关。然而，关于该家族的分子进化模式知之甚少。在这里，我们研究了 EGF-CFC 蛋白在后生动物中的起源、保守程度和进化关系。结果表明，EGF-CFC 基因的首次出现发生在后生动物的祖先中。系统发育分析支持将该家族分为不同的亚家族，这些亚家族似乎是通过谱系特异性复制和分歧进化而来的。对两个主要的哺乳动物同源亚家族（Cripto 和 Cryptic）之间的进化率变化进行的特定部位分析揭示了关键的氨基酸位点，这些位点可能解释了观察到的功能分歧。此外，功能分歧的估计表明，主要位于 CFC 结构域的位点的进化率快速变化可能有助于两个同源物的不同功能特性。
