Phylogenetic analysis of the SINA/SIAH ubiquitin E3 ligase family in Metazoa.
Phylogenetic analysis of the SINA/SIAH ubiquitin E3 ligase family in Metazoa.
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DOI：
10.1186/s12862-017-1024-x
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发表时间：
2017-08-07
影响因子：
3.4
通讯作者：
Tang AH
中科院分区：
文献类型：
--
作者：
Pepper IJ;Van Sciver RE;Tang AH
RAS信号通路是一条重要的发育通路，控制着细胞增殖、分化、运动和凋亡等许多基本的生物学过程。果蝇Seven-IN-Absentia（SINA）是一种泛素E3连接酶，是最下游的信号“看门人”，其生物学活性是正确RAS信号转导所必需的。脊椎动物SINA同源物（SIAH）与果蝇SINA具有高度的氨基酸同源性。SINA/SIAH是经典的EGFR/RAS/RAF/MAPK信号转导通路中最保守的信号组分。脊椎动物SIAH 1、2和3是无脊椎动物SINA蛋白的三个直向同源物。SINA和SIAH 1同源基因存在于后生动物的所有主要分类群中。这些蛋白质具有四个保守的功能结构域，称为RING（真正有趣的新基因），SZF（SIAH型锌指），SBS（底物结合位点）和DIMER（二聚化）。除了siah 1基因，大多数脊椎动物在它们的基因组中编码另外两个siah基因（siah 2和siah 3）。脊椎动物SIAH 2具有高度发散和延伸的N-末端序列，而其RING、SZF、SBS和DIMER结构域与SIAH 1保持高度氨基酸同一性/相似性。但与脊椎动物SIAH 1和SIAH 2不同，SIAH 3缺乏功能性RING结构域，这表明SIAH 3可能是一种失活的E3连接酶。当与SIAH 1和SIAH 2子树相比时，SIAH 3子树表现出高度的氨基酸分歧。我们发现SIAH 1和SIAH 2在迄今为止检查的所有人类上皮细胞系中表达，而SIAH 3仅在有限的癌细胞系亚群中表达。通过系统发育分析的后生动物SINA和SIAH E3连接酶，我们确定了许多不变的和不同的氨基酸残基，以及进化上保守的功能基序在这个医学相关的基因家族。我们对这种独特的后生动物SINA/SIAH蛋白家族的系统医学研究为未来设计针对致癌K-RAS驱动的转移性人类癌症的逻辑、有效和持久的基于抗SIAH的抗癌策略提供了宝贵的基于进化的支持。因此，这种进化研究的方法应该是癌症生物学的兴趣。本文的在线版本（doi：10.1186/s12862-017-1024-x）包含补充材料，可供授权用户使用。
The RAS signaling pathway is a pivotal developmental pathway that controls many fundamental biological processes including cell proliferation, differentiation, movement and apoptosis. Drosophila Seven-IN-Absentia (SINA) is a ubiquitin E3 ligase that is the most downstream signaling “gatekeeper” whose biological activity is essential for proper RAS signal transduction. Vertebrate SINA homologs (SIAHs) share a high degree of amino acid identity with that of Drosophila SINA. SINA/SIAH is the most conserved signaling component in the canonical EGFR/RAS/RAF/MAPK signal transduction pathway. Vertebrate SIAH1, 2, and 3 are the three orthologs to invertebrate SINA protein. SINA and SIAH1 orthologs are found in all major taxa of metazoans. These proteins have four conserved functional domains, known as RING (Really Interesting New Gene), SZF (SIAH-type zinc finger), SBS (substrate binding site) and DIMER (Dimerization). In addition to the siah1 gene, most vertebrates encode two additional siah genes (siah2 and siah3) in their genomes. Vertebrate SIAH2 has a highly divergent and extended N-terminal sequence, while its RING, SZF, SBS and DIMER domains maintain high amino acid identity/similarity to that of SIAH1. But unlike vertebrate SIAH1 and SIAH2, SIAH3 lacks a functional RING domain, suggesting that SIAH3 may be an inactive E3 ligase. The SIAH3 subtree exhibits a high degree of amino acid divergence when compared to the SIAH1 and SIAH2 subtrees. We find that SIAH1 and SIAH2 are expressed in all human epithelial cell lines examined thus far, while SIAH3 is only expressed in a limited subset of cancer cell lines. Through phylogenetic analyses of metazoan SINA and SIAH E3 ligases, we identified many invariant and divergent amino acid residues, as well as the evolutionarily conserved functional motifs in this medically relevant gene family. Our phylomedicinal study of this unique metazoan SINA/SIAH protein family has provided invaluable evolution-based support towards future effort to design logical, potent, and durable anti-SIAH-based anticancer strategies against oncogenic K-RAS-driven metastatic human cancers. Thus, this method of evolutionary study should be of interest in cancer biology. The online version of this article (doi:10.1186/s12862-017-1024-x) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
Mei, Y.;Xie, C.;Wu, M.
通讯作者：
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影响因子：
64.8
作者：
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DOI：
10.1073/pnas.91.24.11689
发表时间：
1994-11-22
影响因子：
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影响因子：
120.1
作者：
Cox, Adrienne D.;Fesik, Stephen W.;Kimmelman, Alec C.;Luo, Ji;Der, Channing J.
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