# SIAH2

## Overview
SIAH2 is a gene that encodes the siah E3 ubiquitin protein ligase 2, a member of the Seven in Absentia Homologs (SIAHs) family of E3 ubiquitin ligases. This protein plays a pivotal role in the ubiquitin-proteasome pathway, which is crucial for regulating protein stability within cells. SIAH2 is particularly significant in the context of hypoxia, where it modulates the stability of prolyl hydroxylases, thereby influencing the levels of hypoxia-inducible factor 1-alpha (HIF1α) and facilitating cellular adaptation to low oxygen conditions (Nakayama2004Siah2). Beyond its role in oxygen homeostasis, SIAH2 is involved in various cellular processes, including cell adhesion, polarity, and stress response pathways, by targeting specific proteins for degradation (Habelhah2002Stressinduced; Kim2013Siah2). The protein's involvement in these pathways underscores its importance in both normal cellular function and disease states, such as cancer, where it is often overexpressed and associated with poor prognosis (Xu2021Regulation; Moreno2015The).

## Structure
The SIAH2 protein is a member of the SIAH family of E3 ubiquitin ligases, characterized by a RING finger domain essential for its ligase activity and a substrate binding domain (SBD) that facilitates interaction with target proteins. The crystal structure of SIAH2 reveals a close resemblance to SIAH1, featuring a C-terminal TNF-receptor associated factor (TRAF)-like SBD and two zinc fingers (ZnFs) (Zhang2017The). The SBD consists of two anti-parallel β-sheets, with ZnF2 tightly packed against it, while ZnF1 is more independent (Zhang2017The). The protein dimerizes through the SBD, and the ZnF domains coordinate zinc ions, playing a role in protein-protein interactions (Zhang2017The).

SIAH2 is involved in the regulation of hypoxia-induced pathways, significant in tumor development, and its activity can be influenced by post-translational modifications such as phosphorylation (Anupriya2011Homology). The protein's stability is slightly lower than that of SIAH1, potentially due to differences in specific residues, such as L250, which forms a hydrophobic core with neighboring residues (Zhang2017The). Mutations in these residues can affect protein stability, and the hydrophobic pocket may play a role in compound binding (Zhang2017The).

## Function
The SIAH2 gene encodes an E3 ubiquitin ligase that plays a critical role in the regulation of protein stability through the ubiquitin-proteasome pathway. In healthy human cells, SIAH2 is involved in maintaining oxygen homeostasis by regulating the stability of prolyl hydroxylases, particularly PHD1 and PHD3, which are crucial for the hydroxylation of hypoxia-inducible factor 1-alpha (HIF1α). Under hypoxic conditions, SIAH2 targets PHD3 for ubiquitination and proteasome-mediated degradation, leading to increased stability and expression of HIF1α, which is essential for cellular adaptation to low oxygen levels (Nakayama2004Siah2).

SIAH2 also regulates cell adhesion and polarity by controlling the stability of the tumor suppressor protein ASPP2. This regulation affects epithelial cell polarity and tight junction integrity, particularly under hypoxic conditions, by modulating the availability of ASPP2 through ubiquitination and degradation (Kim2013Siah2).

Additionally, SIAH2 is involved in stress response pathways by mediating the degradation of TRAF2, a key regulator in cellular responses to stress and cytokines. This process is crucial for modulating TRAF2-dependent signaling pathways, impacting apoptosis and stress kinase regulation (Habelhah2002Stressinduced).

## Clinical Significance
Alterations in the expression of the SIAH2 gene have significant clinical implications in various cancers. SIAH2 is overexpressed in several malignancies, including lung, breast, prostate, pancreatic, and ovarian cancers, where it often acts as an oncogene. In lung cancer, increased SIAH2 expression is associated with higher tumor grade and poor prognosis, particularly in non-small cell lung cancer (NSCLC) (Xu2021Regulation; Moreno2015The). In breast cancer, SIAH2 is linked to aggressive tumor phenotypes and poor treatment outcomes, especially in ER-positive and basal-like subtypes (Chan2011The; Knauer2015The).

SIAH2 also plays a role in the hypoxic response, promoting tumorigenesis by stabilizing HIF-1α, which enhances angiogenesis and tumor growth (Qi2013Regulators; Nakayama2009The). In ovarian cancer, high SIAH2 expression correlates with poor overall and disease-free survival, making it a potential prognostic marker (Gao2016Overexpression). The gene's involvement in the degradation of tumor suppressors and regulation of signaling pathways like Ras/ERK further underscores its role in cancer progression (Xu2021Regulation; Nakayama2009The). These findings suggest that targeting SIAH2 could be a promising strategy for cancer therapy.

## Interactions
SIAH2, a member of the Seven in Absentia Homologs (SIAHs) family of E3 ubiquitin ligases, is involved in various protein interactions that regulate key cellular processes. SIAH2 interacts with prolyl hydroxylases, particularly PHD3, targeting them for ubiquitination and proteasome-mediated degradation. This interaction is crucial for the regulation of hypoxia-inducible factor 1-alpha (HIF-1α) levels under hypoxic conditions, as the degradation of PHD3 by SIAH2 leads to increased HIF-1α expression (Nakayama2004Siah2).

SIAH2 also interacts with the deubiquitinase USP19 through a PxxxVxP consensus motif, which is important for regulating the activity of USP19 and, consequently, the hypoxia pathway (Zhang2017The). The interaction between SIAH2 and USP19 is evolutionarily conserved, indicating its significance in cellular responses to hypoxia (Zhang2017The).

In addition, SIAH2 is involved in the degradation of Sprouty2, a negative regulator of Ras signaling, thereby modulating the MAPK-ERK signaling pathway. This interaction is significant in cancer progression, as it affects cell proliferation and metastasis (Qi2013Regulators). SIAH2's role in these interactions highlights its importance in cellular stress responses and cancer-related pathways.


## References


[1. (Xu2021Regulation) Dazhong Xu and Cen Li. Regulation of the siah2-hif-1 axis by protein kinases and its implication in cancer therapy. Frontiers in Cell and Developmental Biology, March 2021. URL: http://dx.doi.org/10.3389/fcell.2021.646687, doi:10.3389/fcell.2021.646687. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2021.646687)

[2. (Knauer2015The) Shirley K. Knauer, Nisintha Mahendrarajah, Wynand P. Roos, and Oliver H. Krämer. The inducible e3 ubiquitin ligases siah1 and siah2 perform critical roles in breast and prostate cancers. Cytokine & Growth Factor Reviews, 26(4):405–413, August 2015. URL: http://dx.doi.org/10.1016/j.cytogfr.2015.04.002, doi:10.1016/j.cytogfr.2015.04.002. This article has 23 citations.](https://doi.org/10.1016/j.cytogfr.2015.04.002)

[3. (Qi2013Regulators) Jianfei Qi, Hyungsoo Kim, Marzia Scortegagna, and Ze’ev A. Ronai. Regulators and effectors of siah ubiquitin ligases. Cell Biochemistry and Biophysics, 67(1):15–24, May 2013. URL: http://dx.doi.org/10.1007/s12013-013-9636-2, doi:10.1007/s12013-013-9636-2. This article has 57 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12013-013-9636-2)

[4. (Habelhah2002Stressinduced) H. Habelhah. Stress-induced decrease in traf2 stability is mediated by siah2. The EMBO Journal, 21(21):5756–5765, November 2002. URL: http://dx.doi.org/10.1093/emboj/cdf576, doi:10.1093/emboj/cdf576. This article has 102 citations.](https://doi.org/10.1093/emboj/cdf576)

[5. (Moreno2015The) Paula Moreno, Maribel Lara-Chica, Rafael Soler-Torronteras, Teresa Caro, Manuel Medina, Antonio Álvarez, Ángel Salvatierra, Eduardo Muñoz, and Marco A. Calzado. The expression of the ubiquitin ligase siah2 (seven in absentia homolog 2) is increased in human lung cancer. PLOS ONE, 10(11):e0143376, November 2015. URL: http://dx.doi.org/10.1371/journal.pone.0143376, doi:10.1371/journal.pone.0143376. This article has 16 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0143376)

[6. (Zhang2017The) Qi Zhang, Zhongduo Wang, Feng Hou, Rachel Harding, Xinyi Huang, Aiping Dong, John R. Walker, and Yufeng Tong. The substrate binding domains of human siah e3 ubiquitin ligases are now crystal clear. Biochimica et Biophysica Acta (BBA) - General Subjects, 1861(1):3095–3105, January 2017. URL: http://dx.doi.org/10.1016/j.bbagen.2016.10.019, doi:10.1016/j.bbagen.2016.10.019. This article has 21 citations.](https://doi.org/10.1016/j.bbagen.2016.10.019)

[7. (Gao2016Overexpression) Ya Gao, Yunduo Liu, Fanling Meng, Pan Shang, Shuxiang Wang, Yu Zhang, Yuqi Sun, Yuping Wang, Jing Wang, and Xiuwei Chen. Overexpression of siah2 is associated with poor prognosis in patients with epithelial ovarian carcinoma. International Journal of Gynecologic Cancer, 26(1):114–119, January 2016. URL: http://dx.doi.org/10.1097/igc.0000000000000574, doi:10.1097/igc.0000000000000574. This article has 6 citations.](https://doi.org/10.1097/igc.0000000000000574)

[8. (Anupriya2011Homology) Gopalsamy Anupriya, Kothapalli Roopa, S. Basappa, Yap Seng Chong, and Loganath Annamalai. Homology modeling and in silico screening of inhibitors for the substrate binding domain of human siah2: implications for hypoxia-induced cancers. Journal of Molecular Modeling, 17(12):3325–3332, March 2011. URL: http://dx.doi.org/10.1007/s00894-011-1025-4, doi:10.1007/s00894-011-1025-4. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s00894-011-1025-4)

[9. (Chan2011The) Peter Chan, Andreas Möller, Mira CP Liu, Jaclyn E Sceneay, Christina SF Wong, Nic Waddell, Katie T Huang, Alexander Dobrovic, Ewan KA Millar, Sandra A O’Toole, Catriona M McNeil, Robert L Sutherland, David D Bowtell, and Stephen B Fox. The expression of the ubiquitin ligase siah2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression. Breast Cancer Research, February 2011. URL: http://dx.doi.org/10.1186/bcr2828, doi:10.1186/bcr2828. This article has 42 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/bcr2828)

[10. (Nakayama2004Siah2) Koh Nakayama, Ian J Frew, Mette Hagensen, Marianne Skals, Hasem Habelhah, Anindita Bhoumik, Takayuki Kadoya, Hediye Erdjument-Bromage, Paul Tempst, Peter B Frappell, David D Bowtell, and Ze’ev Ronai. Siah2 regulates stability of prolyl-hydroxylases, controls hif1α abundance, and modulates physiological responses to hypoxia. Cell, 117(7):941–952, June 2004. URL: http://dx.doi.org/10.1016/j.cell.2004.06.001, doi:10.1016/j.cell.2004.06.001. This article has 332 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.cell.2004.06.001)

[11. (Kim2013Siah2) H Kim, G Claps, A Möller, D Bowtell, X Lu, and Z A Ronai. Siah2 regulates tight junction integrity and cell polarity through control of aspp2 stability. Oncogene, 33(15):2004–2010, May 2013. URL: http://dx.doi.org/10.1038/onc.2013.149, doi:10.1038/onc.2013.149. This article has 21 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/onc.2013.149)

[12. (Nakayama2009The) Koh Nakayama, Jianfei Qi, and Ze’ev Ronai. The ubiquitin ligase siah2 and the hypoxia response. Molecular Cancer Research, 7(4):443–451, April 2009. URL: http://dx.doi.org/10.1158/1541-7786.mcr-08-0458, doi:10.1158/1541-7786.mcr-08-0458. This article has 101 citations and is from a peer-reviewed journal.](https://doi.org/10.1158/1541-7786.mcr-08-0458)