Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on the interactions of bacterial pathogens with their host have provided an invaluable source of information on the major functions of eukaryotic and prokaryotic cell biology. In addition, this expanding field of research, known as cellular microbiology, has revealed fascinating examples of trans-kingdom functional interplay. Bacterial factors actually exploit eukaryotic cell machineries using refined molecular strategies to promote invasion and proliferation within their host. Here, we review a family of bacterial toxins that modulate their activity in eukaryotic cells by activating Rho GTPases and exploiting the ubiquitin/proteasome machineries. This family, found in human and animal pathogenic Gram-negative bacteria, encompasses the cytotoxic necrotizing factors (CNFs) from Escherichia coli and Yersinia species as well as dermonecrotic toxins from Bordetella species. We survey the genetics, biochemistry, molecular and cellular biology of these bacterial factors from the standpoint of the CNF1 toxin, the paradigm of Rho GTPase-activating toxins produced by urinary tract infections causing pathogenic Escherichia coli. Because it reveals important connections between bacterial invasion and the host inflammatory response, the mode of action of CNF1 and its related Rho GTPase-targetting toxins addresses major issues of basic and medical research and constitutes a privileged experimental model for host-pathogen interaction.
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PMID:Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology. 1768 Aug 7

RhoBTB proteins constitute a subfamily of atypical members within the Rho family of small guanosine triphosphatases (GTPases). Their most salient feature is their domain architecture: a GTPase domain (in most cases, non-functional) is followed by a prolinerich region, a tandem of 2 broadcomplex, tramtrack, bric a brac (BTB) domains, and a conserved Cterminal region. In humans, the RhoBTB subfamily consists of 3 isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. Orthologs are present in several other eukaryotes, such as Drosophila and Dictyostelium, but have been lost in plants and fungi. Interest in RhoBTB arose when RHOBTB2 was identified as the gene homozygously deleted in breast cancer samples and was proposed as a candidate tumor suppressor gene, a property that has been extended to RHOBTB1. The functions of RhoBTB proteins have not been defined yet, but may be related to the roles of BTB domains in the recruitment of cullin3, a component of a family of ubiquitin ligases. A model emerges in which RhoBTB proteins are required to maintain constant levels of putative substrates involved in cell cycle regulation or vesicle transport through targeting for degradation in the 26S proteasome. RhoBTB proteins are engrossing the list of Rho GTPases involved in tumorigenesis. Unlike typical Rho GTPases (usually overexpressed or hyperactive), RhoBTB proteins appear to play a part in the carcinogenic process through a mechanism that involves the decreased or abolished expression of the corresponding genes, or more rarely, mutations that result in impaired functioning of the protein, presumably leading to the accumulation of RhoBTB substrates and alterations of the cellular homeostasis.
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PMID:Rho GTPases of the RhoBTB subfamily and tumorigenesis. 1829 93

The recently identified RhoBTB family is a member of the Rho GTPase family. One family member, RhoBTB2, has been implicated as a tumor suppressor in lung and breast cancer. Studies have shown that RhoBTB2 binds to the ubiquitin ligase scaffold Cul3 and that Cul3 regulates RhoBTB2 protein levels by ubiquitinating RhoBTB2 directly, leading to its degradation by the proteasome. This chapter details the cell biological and biochemical methods for analyzing the regulation of RhoBTB2 by Cul3.
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PMID:Regulation of RhoBTB2 by the Cul3 ubiquitin ligase complex. 1837 59

The small guanosine triphosphate (GTP)-binding proteins of the Rho family are implicated in various cell functions, including establishment and maintenance of cell polarity. Activity of Rho guanosine triphosphatases (GTPases) is not only regulated by guanine nucleotide exchange factors and GTPase-activating proteins but also by guanine nucleotide dissociation inhibitors (GDIs). These proteins have the ability to extract Rho proteins from membranes and keep them in an inactive cytosolic complex. Here, we show that Rdi1, the sole Rho GDI of the yeast Saccharomyces cerevisiae, contributes to pseudohyphal growth and mitotic exit. Rdi1 interacts only with Cdc42, Rho1, and Rho4, and it regulates these Rho GTPases by distinct mechanisms. Binding between Rdi1 and Cdc42 as well as Rho1 is modulated by the Cdc42 effector and p21-activated kinase Cla4. After membrane extraction mediated by Rdi1, Rho4 is degraded by a novel mechanism, which includes the glycogen synthase kinase 3beta homologue Ygk3, vacuolar proteases, and the proteasome. Together, these results indicate that Rdi1 uses distinct modes of regulation for different Rho GTPases.
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PMID:The Rho GDI Rdi1 regulates Rho GTPases by distinct mechanisms. 1841 12

Small GTPases of the Rho family act as molecular switches, and modulation of the GTP-bound state of Rho proteins is a well-characterized means of regulating their signaling activity in vivo. In contrast, the regulation of Rho-type GTPases by posttranslational modifications is poorly understood. Here, we present evidence of the control of the Saccharomyces cerevisiae Rho-type GTPase Rho5p by phosphorylation and ubiquitination. Rho5p binds to Ste50p, and the expression of the activated RHO5(Q91H) allele in an Deltaste50 strain is lethal under conditions of osmotic stress. An overexpression screen identified RGD2 and MSI1 as being high-copy suppressors of the osmotic sensitivity of this lethality. Rgd2p had been identified as being a possible Rho5p GTPase-activating protein based on an in vitro assay; this result supports its function as a regulator of Rho5p activity in vivo. MSI1 was previously identified as being a suppressor of hyperactive Ras/cyclic AMP signaling, where it antagonizes Npr1p kinase activity and promotes ubiquitination. Here, we show that Msi1p also acts via Npr1p to suppress activated Rho5p signaling. Rho5p is ubiquitinated, and its expression is lethal in a strain that is compromised for proteasome activity. These data identify Rho5p as being a target of Msi1p/Npr1p regulation and describe a regulatory circuit involving phosphorylation and ubiquitination.
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PMID:Rho5p is involved in mediating the osmotic stress response in Saccharomyces cerevisiae, and its activity is regulated via Msi1p and Npr1p by phosphorylation and ubiquitination. 1862 25

Proteasome inhibition has been observed in many neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Here, the effect of proteasome inhibition on the morphology of cultured rat cortical astrocytes was investigated. Increasing evidence suggests that the function of astrocytes is related closely to its morphology. Lactacystin, a specific inhibitor of the 20S proteasome, can induce astrocytes stellation in a dose dependent manner and reorganize the cytoskeleton of astrocytes. Furthermore, decreased levels of expression of Rho A, total Akt, and Phospho-Akt were found in the process of astrocytes stellation and lysophosphatidic acid, an activator of Rho A, can largely reverse the astrocytes stellation caused by lactacystin. This suggests that proteasome inhibition in astrocytes could stabilize signals of morphological changes that might be processed through Rho and Akt signaling cascade. Our results suggest that proteasome inhibition might function as a factor regulating astrocytes morphology in some pathophysiological conditions.
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PMID:Lactacystin stimulates stellation of cultured rat cortical astrocytes. 1877 30

Enhancing the degradation of mutant protein is one of the most investigated approaches in experimental therapy of the polyglutamine-related disorders such as Huntington disease (HD). Inhibition of rho-associated kinases (ROCKs) reduced the aggregation and levels of mutant huntingtin in cellular models of HD via activation of the ubiquitin proteasome system (UPS) and macroautophagy. This unique effect makes the Rho/ROCK pathway and its downstream effectors attractive therapeutic targets for polyglutamine-related diseases.
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PMID:Enhanced degradation of mutant huntingtin by rho kinase inhibition is mediated through activation of proteasome and macroautophagy. 1941 23

Net1 is a nuclear Rho guanine nucleotide exchange factor that is specific for the RhoA subfamily of small G proteins. Truncated forms of Net1 are transforming in NIH3T3 cells, and this activity requires cytoplasmic localization of Net1 as well as the presence of a COOH-terminal PDZ binding site. We have previously shown that Net1 interacts with PDZ domain-containing proteins within the Discs Large (Dlg) family and relocalizes them to the nucleus. In the present work, we demonstrate that Net1 binds directly to the first two PDZ domains of Dlg1 and that both PDZ domains are required for maximal interaction in cells. Furthermore, we show that Net1 is an unstable protein in MCF7 breast epithelial cells and that interaction with Dlg1 significantly enhances Net1 stability. Stabilization by Dlg1 significantly increases the ability of Net1 to stimulate RhoA activation in cells. The stability of endogenous Net1 is strongly enhanced by cell-cell contact, and this correlates with a dramatic increase in the interaction between Net1 and Dlg1. Importantly, disruption of E-cadherin-mediated cell contacts, either by depletion of external calcium or by treatment with transforming growth factor beta, leads to a rapid loss of the interaction between Net1 and Dlg1 and a subsequent increase in the ubiquitylation of Net1. These results indicate that Net1 requires interaction with PDZ domain proteins, such as Dlg1, to protect it from proteasome-mediated degradation and to maximally stimulate RhoA and that this interaction is regulated by cell-cell contact.
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PMID:Interaction of the RhoA exchange factor Net1 with discs large homolog 1 protects it from proteasome-mediated degradation and potentiates Net1 activity. 1958 2

p190RhoGAP-A (p190) is a GTPase-activating protein known to regulate actin cytoskeleton dynamics by decreasing RhoGTP levels through activation of Rho intrinsic GTPase activity. We have previously shown that p190 protein levels are cell cycle-regulated, decreasing in mitosis, and that this decrease is mediated by the ubiquitin-proteasome pathway. In addition, overexpression of p190 results in decreased RhoGTP levels at the cleavage furrow during cytokinesis, p190 and the RhoGEF Ect2 play opposing roles in cytokinesis, and sustained levels of p190 in mitosis are associated with cytokinesis failure, all findings that suggest but do not directly demonstrate that completion of cytokinesis is dependent on reduced levels of p190. Here we report, using an RNAi reconstitution approach with a degradation-resistant mutant, that decreased p190 levels are required for successful cytokinesis. We also show that the multinucleation phenotype is dependent on p190 RhoGAP activity, determine that the N-terminal GBDS1 region is necessary and sufficient for p190 mitotic ubiquitination and degradation, and identify four N-terminal residues as necessary for the degradation of p190 in mitosis. Our data indicate that in addition to activation of RhoGEF(s), reduction of RhoGAP (p190) is a critical mechanism by which increased RhoGTP levels are achieved in late mitosis, thereby ensuring proper cell division.
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PMID:Mitotic down-regulation of p190RhoGAP is required for the successful completion of cytokinesis. 2053 86

Most Rho family GTPases serve as key molecular switches in a wide spectrum of biological processes. An increasing number of studies have expanded their roles to the spermatogenesis. Several members of Rho family have been confirmed to be essential for mammalian spermatogenesis, but the precise roles of this family in male reproduction have not been well studied yet. Here we report a surprising function of an atypical and testis-specific Rho GTPase, RSA-14-44 in spermatogenesis. Featured by unique structural and expressional patterns, RSA-14-44 is distinguished from three canonical members of Rho cluster. Thus, we define RSA-14-44 as a new member of Rho GTPases family and rename it RhoS (Rho in spermatogenic cells). RhoS associates with PSMB5, a catalytic subunit of the proteasome, in a series of stage-specific spermatogenic cells. More importantly, RhoS does not directly modulate the cellular proteasome activity, but participates in regulating the stability of "unincorporated" PSMB5 precursors. Meanwhile, our data demonstrate that the activation of RhoS is prerequisite for negatively regulating the stability of PSMB5 precursors. Therefore, our finding uncovers a direct and functional connection between the Rho GTPase family and the pathway of proteasome biogenesis and provide new clues for deciphering the secrets of spermatogenesis.
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PMID:A novel testis-specific GTPase serves as a link to proteasome biogenesis: functional characterization of RhoS/RSA-14-44 in spermatogenesis. 2098 Jun 21


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