BTB proteins as henchmen of Cul3-based ubiquitin ligases

Krek, Wilhelm

doi:10.1038/ncb1103-950

Cited by 55 publications

(51 citation statements)

References 14 publications

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“…BTB-domain containing proteins have recently been identified as substrate-specific adaptors for ubiquitin ligase complexes that contain the scaffolding protein Cul3 (28,29). We demonstrate here that the Pcif1-Cul3 complex targets Pdx1 protein for ubiquitination and proteasomal degradation.…”

Section: Introductionmentioning

confidence: 72%

Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice

Claiborn¹,

Sachdeva²,

Cannon³

et al. 2010

J. Clin. Invest.

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The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1 +/-mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1 +/-mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis.

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Section: Introductionmentioning

confidence: 72%

Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice

Claiborn¹,

Sachdeva²,

Cannon³

et al. 2010

J. Clin. Invest.

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“…To better understand the function and regulation of nuclear phosphoinositide signaling pathways, we sought to identify proteins that interact with PIPKII␤. Yeast two-hybrid screening identified an interaction between PIPKII␤ and speckle-type POZ domain protein (SPOP), a nuclear speckle-associated BTB domain protein, and substrate adaptor for Cul3-based ubiquitin ligases (13,14,16,17,19). We demonstrate that PIPKII␤ and SPOP interact in vitro and in vivo and co-localize at nuclear speckles in HeLa cells.…”

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confidence: 95%

“…Cul3-based ubiquitin ligases are an emerging member of this family (13)(14)(15)(16). Substrate specificity of Cul3-based ubiquitin ligases is dictated by BTB (Broad complex/ Tramtrack/bric-a-brac) domain-containing proteins that bind directly to Cul3 through their BTB domain and bind substrates through a second protein-protein interaction domain (13,14,16,17). Orthologs of Cul3 and BTB proteins have been identified in eukaryotes ranging from Caenorhabditis elegans to humans, and several substrates of Cul3-based ligases have been identified (18 -20).…”

mentioning

confidence: 99%

Coordinated Activation of the Nuclear Ubiquitin Ligase Cul3-SPOP by the Generation of Phosphatidylinositol 5-Phosphate

Bunce

Boronenkov

Anderson

2008

Journal of Biological Chemistry

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Phosphoinositide signaling pathways regulate numerous processes in eukaryotic cells, including migration, proliferation, and survival. The regulatory lipid phosphatidylinositol 4,5-bisphosphate is synthesized by two distinct classes of phosphatidylinositol phosphate kinases (PIPKs), the type I and II PIPKs. Although numerous physiological functions have been identified for type I PIPKs, little is known about the functions and regulation of type II PIPK. Using a yeast two-hybrid screen, we identified an interaction between the type II␤ PIPK isoform (PIPKII␤) and SPOP (speckle-type POZ domain protein), a nuclear speckle-associated protein that recruits substrates to Cul3-based ubiquitin ligases. PIPKII␤ and SPOP interact and co-localize at nuclear speckles in mammalian cells, and SPOP mediates the ubiquitylation of PIPKII␤ by Cul3-based ubiquitin ligases. Additionally, stimulation of the p38 MAPK pathway enhances the ubiquitin ligase activity of Cul3-SPOP toward multiple substrate proteins. Finally, a kinase-dead PIPKII␤ mutant enhanced ubiquitylation of Cul3-SPOP substrates. The kinase-dead PIPKII␤ mutant increases the cellular content of its substrate lipid phosphatidylinositol 5-phosphate (PI5P), suggesting that PI5P may stimulate Cul3-SPOP activity through a p38-dependent signaling pathway. Expression of phosphatidylinositol-4,5-bisphosphate 4-phosphatases that generate PI5P dramatically stimulated Cul3-SPOP activity and was blocked by the p38 inhibitor SB203580. Taken together, these data define a novel mechanism whereby the phosphoinositide PI5P leads to stimulation of Cul3-SPOP ubiquitin ligase activity and also implicate PIPKII␤ as a key regulator of this signaling pathway through its association with the Cul3-SPOP complex.Phosphoinositide signaling pathways modulate a diverse array of cellular processes in eukaryotes. Modification of the inositol ring by lipid kinases and phosphatases produces distinct phosphatidylinositol phosphate (PIP) 2 isomers. These phosphatidylinositol phosphate isomers in turn selectively modulate the activities of effector proteins. In the cytosol, phosphoinositides regulate numerous processes, including actin polymerization, focal adhesion dynamics, ion channel activity, growth factor receptor signaling, and vesicle trafficking (1-4).In the nucleus, an autonomous phosphoinositide cycle regulates processes, including differentiation, proliferation, cell cycle progression, and apoptosis (5). Phosphatidylinositol 4,5-bisphosphate (PI-4,5-P 2 ) is a critical phosphoinositide in eukaryotic cells. PI-4,5-P 2 is not only itself a potent signaling molecule but is also a precursor of other second messengers such as phosphatidylinositol 3,4,5-trisphosphate, inositol 1,4,5-trisphosphate, and diacylglycerol. Because of its multipotent signaling capacity, the regulated synthesis of PI-4,5-P 2 is essential for eukaryotes. In mammalian cells, PI-4,5-P 2 is synthesized by two classes of phosphatidylinositol phosphate kinases (PIPKs) (6). Type I PIPKs (PIPKIs) preferentially use phosphatidylinos...

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“…Although the functional role(s) of these domains are not fully understood at present, the coiled-coil region of NPH3 is known to be necessary and sufficient for interaction with phot1 (10), whereas the BTB domain has been shown recently to interact with CULLIN3 (CUL3) in a heterologous insect cell expression system. 3 Based on paradigms established in fungal and animal systems, in which BTB domain-containing proteins function as substrate adapters in CUL3-based ubiquitin-protein ligase (E3) (21)(22)(23)(24)(25), it has been proposed that NPH3 may function as a core component of a CUL3-based E3 complex that is necessary for phototropic signal progression (5). Although this hypothesis is currently under investigation, the physical and genetic interactions between phot1 and NPH3 suggest that, whatever the biochemical function of NPH3, it will somehow be regulated by phot1.…”

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confidence: 99%

Regulation of Phototropic Signaling in Arabidopsis via Phosphorylation State Changes in the Phototropin 1-interacting Protein NPH3

Pedmale

Liscum

2007

Journal of Biological Chemistry

141

187

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Phototropism, or the directional growth (curvature) of various organs toward or away from incident light, represents a ubiquitous adaptive response within the plant kingdom. This response is initiated through the sensing of directional blue light (BL) by a small family of photoreceptors known as the phototropins. Of the two phototropins present in the model plant Arabidopsis thaliana, phot1 (phototropin 1) is the dominant receptor controlling phototropism. Absorption of BL by the sensory portion of phot1 leads, as in other plant phototropins, to activation of a C-terminal serine/threonine protein kinase domain, which is tightly coupled with phototropic responsiveness. Of the five phot1-interacting proteins identified to date, only one, NPH3 (non-phototropic hypocotyl 3), is essential for all phot1-dependent phototropic responses, yet little is known about how phot1 signals through NPH3. Here, we show that, in dark-grown seedlings, NPH3 exists as a phosphorylated protein and that BL stimulates its dephosphorylation. phot1 is necessary for this response and appears to regulate the activity of a type 1 protein phosphatase that catalyzes the reaction. The abrogation of both BL-dependent dephosphorylation of NPH3 and development of phototropic curvatures by protein phosphatase inhibitors further suggests that this post-translational modification represents a crucial event in phot1-dependent phototropism. Given that NPH3 may represent a core component of a CUL3-based ubiquitin-protein ligase (E3), we hypothesize that the phosphorylation state of NPH3 determines the functional status of such an E3 and that differential regulation of this E3 is required for normal phototropic responsiveness.

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BTB proteins as henchmen of Cul3-based ubiquitin ligases

Cited by 55 publications

References 14 publications

Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice

Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice

Coordinated Activation of the Nuclear Ubiquitin Ligase Cul3-SPOP by the Generation of Phosphatidylinositol 5-Phosphate

Regulation of Phototropic Signaling in Arabidopsis via Phosphorylation State Changes in the Phototropin 1-interacting Protein NPH3

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