Regulators and Effectors of Siah Ubiquitin Ligases

Qi, Jianfei; Kim, Hyungsoo; Scortegagna, Marzia; Ronai, Ze’ev A.

doi:10.1007/s12013-013-9636-2

Cited by 66 publications

(117 citation statements)

References 89 publications

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“…In addition to AR signaling, Siah2 has been shown to regulate several other signaling pathways (such as hypoxia signaling and MAPK signaling, among others) that are important for cancer development and progression (10,15,16,18). We demonstrate here that the mutual regulation between Siah2 and AKR1C3 promotes the Siah2-dependent regulation of AR signaling in the AR-positive Rv1 cells.…”

Section: Discussionmentioning

confidence: 63%

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The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Fan

Peng

Hussain

et al. 2015

Journal of Biological Chemistry

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Background: Ubiquitin ligase Siah2 promotes activity of androgen receptor (AR) in prostate cancer cells. Results:The steroidogenic enzyme AKR1C3 binds and stabilizes Siah2 by blocking Siah2 self-ubiquitination and degradation. Conclusion: We identified a catalytic independent role for AKR1C3 on AR activity via Siah2. Significance: The findings may provide new targets for development of AKR1C3 inhibitors as prostate cancer therapy.

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Section: Discussionmentioning

confidence: 63%

“…Siah proteins induce ubiquitination and subsequent degradation of several substrates and thus regulate numerous signaling pathways and biological processes (10). Like other ubiquitin ligases (11), Siah can also self-ubiquitinate and promote its own degradation through the ubiquitin-proteasome pathway (12,13).…”

mentioning

confidence: 99%

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

Fan

Peng

Hussain

et al. 2015

Journal of Biological Chemistry

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“…It is becoming increasingly clear that Siah may have a dual role, as both a tumor suppressor and an oncogene in cancer [17, 40]. Our work suggests that Siah may be acting as a tumor suppressor in the context of EMT and metastasis via suppression of Zeb1.…”

Section: Discussionmentioning

confidence: 68%

The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer

et al. 2014

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Elucidating the mechanisms that underlie metastasis is of paramount importance to understanding tumor progression and to the development of novel therapeutics. Epithelial to Mesenchymal Transition (EMT) plays a vital role in tumor cell dissemination and is regulated by a core cassette of transcription factors. Despite recent advances, the molecular pathways that regulate the EMT program have not yet been fully delineated. We show that Siah ubiquitin ligases regulate Zeb1 protein, a key EMT transcription factor. The induction of EMT in breast cancer cells leads to the down-regulation of Siah, while the loss of Siah induces a mesenchymal phenotype, concurrent with an up-regulation of Zeb1. Overexpression of Siah in vitro mediates Zeb1 degradation, which can be blocked with a Siah peptide inhibitor. Thus, this work demonstrates that Siah is a novel regulator of EMT. This work is the first to identify a mechanism of post-translational regulation of the key Epithelial to Mesenchymal Transition transcription factor Zeb1.

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“…The inherent flexibility and complexity of the system are underscored by multiple phosphosites and docking motifs for multiple kinases being located within this long disordered region, which allows regulation of the same E3 ligase by different pathways. Siah2 phosphorylation can also be mediated by other kinases, including c-Jun N-terminal kinase, dual specificity tyrosine phosphorylation-regulated kinase 2, and homeodomain-interacting protein kinase 2, which can phosphorylate similar motifs within the disordered N terminus of Siah2 (43). Nucleocytoplasmic shuttling of the yeast E3 Rsp5 (44), von Hippel-Lindau protein (45), hRPF1/Nedd4 (46), the RING-IBR protein RBCK1 (47), and muscle-specific E3 MAFbx/Atrogin 1 (48) via NLS and NES signals (often in disordered regions and regulated by phosphorylation) provides other examples of the regulation of E3 activity via cellular localization.…”

Section: Ptms In Disordered Regions Regulate the Subcellular Localizamentioning

confidence: 99%

Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System

Guharoy

Bhowmick

Tompa

2016

Journal of Biological Chemistry

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The ubiquitin-proteasome system (UPS) regulates diverse cellular pathways by the timely removal (or processing) of proteins. Here we review the role of structural disorder and conformational flexibility in the different aspects of degradation. First, we discuss post-translational modifications within disordered regions that regulate E3 ligase localization, conformation, and enzymatic activity, and also the role of flexible linkers in mediating ubiquitin transfer and reaction processivity. Next we review well studied substrates and discuss that substrate elements (degrons) recognized by E3 ligases are highly disordered: short linear motifs recognized by many E3s constitute an important class of degrons, and these are almost always present in disordered regions. Substrate lysines targeted for ubiquitination are also often located in neighboring regions of the E3 docking motifs and are therefore part of the disordered segment. Finally, biochemical experiments and predictions show that initiation of degradation at the 26S proteasome requires a partially unfolded region to facilitate substrate entry into the proteasomal core.Many cellular pathways and regulatory networks require spatial and temporal control of effector protein levels. Regulated degradation mediated by the ubiquitin-proteasome system (UPS) 3 is an important post-translational mechanism that helps to achieve precise fine-tuning of protein levels and is being increasingly linked to more and more pathways. The UPS is the major intracellular degradation pathway that has evolved into a complex system consisting of several hundred dedicated components (1). Important examples of regulated degradation include cell cycle regulatory proteins (e.g. cyclins, cyclin-dependent kinase inhibitors, etc.) that need to be degraded or inactivated before cell cycle checkpoint mechanisms decide upon progress (2, 3). Transcription factors (e.g. mammalian Myc, Jun, E2-F, p53, etc.) that activate gene expression triggered by specific stimuli are usually maintained at low levels (4, 5); further, the ubiquitin system also triggers processing (by limited proteolysis) and activation of transcription factors such as NFB (6). Cell surface growth factor/hormone receptors undergo internalization and degradation to switch off signaling inputs (7-12). The UPS also tightly regulates other key intracellular effectors (e.g. Smad proteins, Bcl-2) of signaling pathways (13-15). Not surprisingly, defects in regulated degradation are being linked to increasing numbers of diseases, including neurodegeneration and cancer, making the UPS very attractive for drug design (16 -19).Ubiquitination is organized as a cascade of E1 (ubiquitinactivating), E2 (ubiquitin-conjugating), and E3 (ubiquitin ligase) enzymes. The pathway is strongly conserved from yeast to mammals. The E1-E2-E3 axis has a pyramidal structure, with 2 E1 proteins (in humans), 30 -40 E2 enzymes, and Ͼ600 E3 ligases (20). E3s are subclassified into major groups based on their subunit organization and domain composition ( Fig. 1) (21,...

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Regulators and Effectors of Siah Ubiquitin Ligases

Cited by 66 publications

References 89 publications

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells

The ubiquitin ligase Siah is a novel regulator of Zeb1 in breast cancer

Design Principles Involving Protein Disorder Facilitate Specific Substrate Selection and Degradation by the Ubiquitin-Proteasome System

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