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Gene Review

SIAH2  -  siah E3 ubiquitin protein ligase 2

Homo sapiens

Synonyms: E3 ubiquitin-protein ligase SIAH2, Seven in absentia homolog 2, Siah-2, hSiah2
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Disease relevance of SIAH2

  • Independent studies have shown that Sina and its highly related mammalian homologues Siah-1 and Siah-2 bind to the DCC (deleted in colorectal cancer) protein and promote its proteolysis via the ubiquitin-proteasome pathway [1].
  • The RING finger ubiquitin ligase Siah2 controls the stability of various substrates involved in stress and hypoxia responses, including the PHD3, which controls the stability of HIF-1alpha [2].

High impact information on SIAH2

  • New evidence suggests that at least two members of the family of hypoxia-inducible factor (HIF) prolyl hydroxylases that regulate HIF stability in response to oxygen (O2) availability are also targeted for proteosome-dependent degradation by the E3 ubiquitin ligases Siah1a and Siah2 [3].
  • Siah2 null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin [4].
  • On the other hand, XRINGO degradation after meiosis I is mediated by the ubiquitin ligase Siah-2, which probably requires phosphorylation of XRINGO on Ser 243 and may be important for the omission of S phase at the meiosis-I-meiosis-II transition in Xenopus oocytes [5].
  • Treatment with proteasomal inhibitor or with small interfering RNA against Siah2 prevented the down-regulation of N-CoR by estrogen [6].
  • These findings reveal that, although estrogen directly regulates the transcription of many genes, by regulating a gene such as Siah2 it can exert profound "secondary" effects on cellular activity through mechanisms such as targeting regulatory proteins for degradation [6].

Biological context of SIAH2

  • SIAH2 maps to chromosome 3q25 and encodes a 324-amino-acid protein that shares 68% identity with Drosophila SINA and 77% identity with human SIAH1 [7].
  • Of seven ESTs mapping to the initial critical region, WI-11588 and SHGC-133 represent the human SIAH2 gene, which was excluded as a candidate for USH3 by sequencing and subsequently, by its position [8].
  • Unlike c-Cbl-mediated degradation of Spry2, SIAH2-mediated degradation was independent of phosphorylation of Spry2 on Tyr55 [9].
  • This effect is attributable to estrogen up-regulation of the ubiquitin ligase Siah2, which is a rapid and primary transcriptional response mediated by the ER, and precedes the loss of N-CoR [6].
  • Siaz shares high sequence homology with vertebrate Siah-2 [10].

Anatomical context of SIAH2


Co-localisations of SIAH2


Other interactions of SIAH2


  1. Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Hu, G., Fearon, E.R. Mol. Cell. Biol. (1999) [Pubmed]
  2. Regulation of the Ring Finger E3 Ligase Siah2 by p38 MAPK. Khurana, A., Nakayama, K., Williams, S., Davis, R.J., Mustelin, T., Ronai, Z. J. Biol. Chem. (2006) [Pubmed]
  3. Siah proteins, HIF prolyl hydroxylases, and the physiological response to hypoxia. Simon, M.C. Cell (2004) [Pubmed]
  4. Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Nakayama, K., Frew, I.J., Hagensen, M., Skals, M., Habelhah, H., Bhoumik, A., Kadoya, T., Erdjument-Bromage, H., Tempst, P., Frappell, P.B., Bowtell, D.D., Ronai, Z. Cell (2004) [Pubmed]
  5. Meiotic regulation of the CDK activator RINGO/Speedy by ubiquitin-proteasome-mediated processing and degradation. Gutierrez, G.J., V??gtlin, A., Castro, A., Ferby, I., Salvagiotto, G., Ronai, Z., Lorca, T., Nebreda, A.R. Nat. Cell Biol. (2006) [Pubmed]
  6. Estrogen down-regulation of the corepressor N-CoR: mechanism and implications for estrogen derepression of N-CoR-regulated genes. Frasor, J., Danes, J.M., Funk, C.C., Katzenellenbogen, B.S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  7. Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Hu, G., Chung, Y.L., Glover, T., Valentine, V., Look, A.T., Fearon, E.R. Genomics (1997) [Pubmed]
  8. A sequence-ready map of the Usher syndrome type III critical region on chromosome 3q. Joensuu, T., Hämäläinen, R., Lehesjoki, A.E., de la Chapelle, A., Sankila, E.M. Genomics (2000) [Pubmed]
  9. Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. Nadeau, R.J., Toher, J.L., Yang, X., Kovalenko, D., Friesel, R. J. Cell. Biochem. (2007) [Pubmed]
  10. The RING domain of Siaz, the zebrafish homologue of Drosophila seven in absentia, is essential for cellular growth arrest. Ro, H., Jang, Y., Rhee, M. Mol. Cells (2004) [Pubmed]
  11. hSiah2 is a new Vav binding protein which inhibits Vav-mediated signaling pathways. Germani, A., Romero, F., Houlard, M., Camonis, J., Gisselbrecht, S., Fischer, S., Varin-Blank, N. Mol. Cell. Biol. (1999) [Pubmed]
  12. Regulation of BOB.1/OBF.1 stability by SIAH. Boehm, J., He, Y., Greiner, A., Staudt, L., Wirth, T. EMBO J. (2001) [Pubmed]
  13. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Liani, E., Eyal, A., Avraham, E., Shemer, R., Szargel, R., Berg, D., Bornemann, A., Riess, O., Ross, C.A., Rott, R., Engelender, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
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