Abstract
BackgroundThe 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.ResultsVertebrate 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.ConclusionThrough 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.
Highlights
The rat sarcoma viral oncogene (RAS) signaling pathway is a pivotal developmental pathway that controls many fundamental biological processes including cell proliferation, differentiation, movement and apoptosis
Phylogenetic analysis of the SINA/SINA homolog (SIAH) family of E3 ligases We retrieved all currently existing SINA/SIAH amino acid sequences from the NCBI Refseq protein database by conducting separate BLAST searches using Drosophila SINA along with human SIAH1, SIAH2, and SIAH3 fulllength proteins as the query sequences
Our findings show that siah1 and siah2 mRNA transcripts are Discussion The field of cancer biology desperately needs a more effective method for controlling and conquering oncogenic Kirsten rat sarcoma viral oncogene (K-RAS) hyperactivation in metastatic human cancer
Summary
The RAS signaling pathway is a pivotal developmental pathway that controls many fundamental biological processes including cell proliferation, differentiation, movement and apoptosis. Drosophila Seven-INAbsentia (SINA) is a ubiquitin E3 ligase that is the most downstream signaling “gatekeeper” whose biological activity is essential for proper RAS signal transduction. SINA/SIAH is the most conserved signaling component in the canonical EGFR/RAS/RAF/MAPK signal transduction pathway. The RAS signaling pathway in metazoans is one of the most fundamental and evolutionarily conserved signaling pathways controlling cell proliferation, motility, and stem cell renewal during normal development, tissue regeneration, and pathogenesis [1,2,3,4,5]. Inhibiting oncogenic K-RAS pathway activation is a logical strategy to stop tumor progression and prevent metastasis in human cancer [8,9,10]. Alternative anti-K-RAS strategies are urgently needed to shutdown “undruggable” oncogenic K-RAS activation and eradicate oncogenic K-RAS-driven metastatic cancer in the clinic [10].
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