Regulation of 2-Oxoglutarate (α-Ketoglutarate) Dehydrogenase Stability by the RING Finger Ubiquitin Ligase Siah

Habelhah, Hasem; Laine, Aaron; Erdjument‐Bromage, Hediye; Tempst, Paul; Gershwin, M. Eric; Bowtell, David D.L.; Ronai, Ze’ev A.

doi:10.1074/jbc.m410315200

Cited by 50 publications

(44 citation statements)

References 28 publications

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“…Somewhat similar to PHYL is Siahinteracting protein (SIP), which interacts with Siah within the same structural domain (3,4). In mammals, two isoforms, Siah1 and Siah2 (5), have been shown to control the stability of several substrates, including nuclear corepressor, ␤-catenin, TRAF2, ␣-ketoglutarate dehydrogenase, and prolyl hydroxylase 3 (PHD3), thereby affecting diverse cellular functions, such as signaling, survival, and mitochondrial biogenesis (6)(7)(8)(9)(10). We have demonstrated that by regulating PHD3 stability, Siah2 contributes to the abundance of hypoxia-inducible factor (HIF)-1␣, thereby playing an important role in the cellular response to hypoxia (9).…”

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confidence: 99%

The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Qi¹,

Nakayama²,

Gaitonde³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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116

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The ubiquitin ligase Siah2 has been shown to regulate prolyl hydroxylase 3 (PHD3) stability with concomitant effect on HIF-1␣ availability. Because HIF-1␣ is implicated in tumorigenesis and metastasis, we used SW1 mouse melanoma cells, which develop primary tumors with a propensity to metastasize, in a syngeneic mouse model to assess a possible role for Siah2 in these processes. Inhibiting Siah2 activity by expressing a peptide designed to outcompete association of Siah2-interacting proteins reduced metastasis through HIF-1␣ without affecting tumorigenesis. Conversely, inhibiting Siah2 activity by means of a dominant-negative Siah2 RING mutant primarily reduced tumorigenesis through the action of Sprouty 2, a negative regulator of Ras signaling. Consistent with our findings, reduced expression of PHD3 and Sprouty2 was observed in more advanced stages of melanoma tumors. Using complementary approaches, our data establish the role of Siah2 in tumorigenesis and metastasis by HIF-dependent and -independent mechanisms.HIF ͉ hypoxia ͉ Siah ͉ Sprouty ͉ prolyl hydroxylase

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confidence: 99%

The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Qi¹,

Nakayama²,

Gaitonde³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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116

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“…Several substrates of the Siah/SINA proteins have been identified and most have been shown to be degraded in an Ub-dependent fashion. Among the substrates are key transcription factors but also cytoplasmic and membrane proteins (Susini et al, 2001;Habelhah et al, 2004;Kim et al, 2004).…”

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confidence: 99%

Seven in Absentia Proteins Affect Plant Growth and Nodulation inMedicago truncatula

et al. 2008

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Protein ubiquitination is a posttranslational regulatory process essential for plant growth and interaction with the environment. E3 ligases, to which the seven in absentia (SINA) proteins belong, determine the specificity by selecting the target proteins for ubiquitination. SINA proteins are found in animals as well as in plants, and a small gene family with highly related members has been identified in the genome of rice (Oryza sativa), Arabidopsis (Arabidopsis thaliana), Medicago truncatula, and poplar (Populus trichocarpa). To acquire insight into the function of SINA proteins in nodulation, a dominant negative form of the Arabidopsis SINAT5 was ectopically expressed in the model legume M. truncatula. After rhizobial inoculation of the 35S:SINAT5DN transgenic plants, fewer nodules were formed than in control plants, and most nodules remained small and white, a sign of impaired symbiosis. Defects in rhizobial infection and symbiosome formation were observed by extensive microscopic analysis. Besides the nodulation phenotype, transgenic plants were affected in shoot growth, leaf size, and lateral root number. This work illustrates a function for SINA E3 ligases in a broad spectrum of plant developmental processes, including nodulation.

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“…Sina/Siah proteins are E3 ligases, acting either as single proteins or as part of a multiprotein complex that is analogous to the Skp1-cullin-1-F-box (SCF) complex. Among the targets of Sina/Siah are NcoR (6), DCC (7), c-Myb (8), BOB-1/OBF-1 (9, 10), Peg3/Pw1 (11), Kid (12), Numb (13), synaptophysin (14), group 1 metabotropic glutamate receptors (15), promyelocytic leukemia protein (16), CtIP (17,34), ␣-synuclein (18), synphilin-1 (18,19), PEG10 (20), T-STAR (21), AF4 (22,23), prolyl-hydroxylase domain proteins (24), and ␣-ketoglutarate dehydrogenase (25). In addition, Siah interacts with adenomatous polyposis coli, a tumor suppressor involved in colon cancers (26); VAV, a nucleotide exchange factor involved in control of Rho/Rac proteins (27); BAG-1, a Hsp70/Hsc70-binding protein that modulates pathways involved in the control of cell proliferation, death, and migration (28,29); and Dab-1, an inhibitor of Siah1 (30).…”

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confidence: 99%

Structural Analysis of Siah1-Siah-interacting Protein Interactions and Insights into the Assembly of an E3 Ligase Multiprotein Complex

Santelli

Leone

et al. 2005

Journal of Biological Chemistry

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Siah1 is the central component of a multiprotein E3 ubiquitin ligase complex that targets ␤-catenin for destruction in response to p53 activation. The E3 complex comprises, in addition to Siah1, Siah-interacting protein (SIP), the adaptor protein Skp1, and the F-box protein Ebi. Here we show that SIP engages Siah1 by means of two elements, both of which are required for mediating ␤-catenin destruction in cells. An N-terminal dimerization domain of SIP sits across the saddle-shaped upper surface of Siah1, with two extended legs packing against the sides of Siah1 by means of a consensus PXAXVXP motif that is common to a family of Siah-binding proteins. The C-terminal domain of SIP, which binds to Skp1, protrudes from the lower surface of Siah1, and we propose that this surface provides the scaffold for bringing substrate and the E2 enzyme into apposition in the functional complex.Polyubiquitination of specific proteins in cells involves the concerted action of E1, 5 E2, and E3 enzymes. First, E1 covalently binds and activates ubiquitin for subsequent transfer to one of several E2s. The latter can in turn directly transfer its bound ubiquitin to the amino groups of lysine side chains in target proteins. More often, however, E3 ligases recognize substrates and direct their interaction with E2s, resulting in the highly specific regulation of target protein polyubiquitination (1, 2). Humans carry two highly related genes, siah1 and siah2 (3), that encode the mammalian homologs of the Drosophila Sina protein, which is required for R7 photoreceptor cell differentiation within the sevenless pathway (4, 5). Sina/Siah proteins are E3 ligases, acting either as single proteins or as part of a multiprotein complex that is analogous to the Skp1-cullin-1-F-box (SCF) complex. Among the targets of Sina/Siah are NcoR (6), DCC (7), c-Myb (8), BOB-1/OBF-1 (9, 10), Peg3/Pw1 (11), Kid (12), Numb (13) (24), and ␣-ketoglutarate dehydrogenase (25). In addition, Siah interacts with adenomatous polyposis coli, a tumor suppressor involved in colon cancers (26); VAV, a nucleotide exchange factor involved in control of Rho/Rac proteins (27); BAG-1, a Hsp70/Hsc70-binding protein that modulates pathways involved in the control of cell proliferation, death, and migration (28, 29); and Dab-1, an inhibitor of Siah1 (30). However, Sina/Siah does not appear to target phyllopod, adenomatous polyposis coli, VAV, BAG-1, or Dab-1 for polyubiquitination and degradation. Thus, not all Siahbinding proteins are targets of Siah-mediated degradation.Recently, we discovered a novel pathway for ␤-catenin degradation involving a complex formed by Siah1, SIP, the adaptor protein Skp1 that is common to the SCF complex, and the F-box protein Ebi that binds ␤-catenin independent of phosphorylation (31). Siah1 expression is upregulated by p53, revealing a link between genotoxic injury and destruction of ␤-catenin, reduced Tcf/LEF activity, and cell cycle arrest (31). Siah1 is a dimeric protein that contains an N-terminal RING domain (an E2 binding domain) followed by...

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Regulation of 2-Oxoglutarate (α-Ketoglutarate) Dehydrogenase Stability by the RING Finger Ubiquitin Ligase Siah

Cited by 50 publications

References 28 publications

The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

The ubiquitin ligase Siah2 regulates tumorigenesis and metastasis by HIF-dependent and -independent pathways

Seven in Absentia Proteins Affect Plant Growth and Nodulation inMedicago truncatula

Structural Analysis of Siah1-Siah-interacting Protein Interactions and Insights into the Assembly of an E3 Ligase Multiprotein Complex

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