Developmentally regulated GTPases: structure, function and roles in disease

AbstractGTPases are a large superfamily of evolutionarily conserved proteins involved in a variety of fundamental cellular processes. The developmentally regulated GTP-binding protein (DRG) subfamily of GTPases consists of two highly conserved paralogs, DRG1 and DRG2, both of which have been implicated in the regulation of cell proliferation, translation and microtubules. Furthermore, DRG1 and 2 proteins both have a conserved binding partner, DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively, that prevents them from being degraded. Similar to DRGs, the DFRP proteins have also been studied in the context of cell growth control and translation. Despite these proteins having been implicated in several fundamental cellular processes they remain relatively poorly characterized, however. In this review, we provide an overview of the structural biology and biochemistry of DRG GTPases and discuss current understanding of DRGs and DFRPs in normal physiology, as well as their emerging roles in diseases such as cancer.

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Bacterial activation of β-catenin signaling in human epithelia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00498.2003 ◽

2004 ◽

Vol 287 (1) ◽

pp. G220-G227 ◽

Cited By ~ 73

Author(s):

Jun Sun ◽

Michael E. Hobert ◽

Anjali S. Rao ◽

Andrew S. Neish ◽

James L. Madara

Keyword(s):

Cell Proliferation ◽

Epithelial Cell ◽

Transcriptional Activation ◽

Growth Control ◽

Effector Protein ◽

Epithelial Cell Proliferation ◽

Gut Flora ◽

T Cell Factor ◽

Mucosal Lining ◽

Cell Growth Control

The mucosal lining of the human intestine is constantly bathed in a milieu of commensal gut flora, the vast majority of these being nonpathogenic microorganisms. Here, we demonstrate that microbial-epithelial cell interactions not only affect proinflammatory pathways but also influence β-catenin signaling, a key component in regulating epithelial cell proliferation. The nonpathogenic Salmonella strain PhoPc activates the β-catenin signaling pathway of human epithelia via a blockade of β-catenin degradation. Normal β-catenin ubiquitination necessary for constitutive β-catenin degradation is abolished, allowing the accumulation and translocation of β-catenin to the nucleus. Transcriptional activation mediated by the β-catenin/T cell factor complex increases c-myc expression and enhances cell proliferation. We also show that the Salmonella effector protein AvrA is involved in modulating this β-catenin activation. These data suggest that nonvirulent bacterial-epithelial interactions can influence β-catenin signaling and cell growth control in a manner previously unsuspected.

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Drosophila Med6 Is Required for Elevated Expression of a Large but Distinct Set of Developmentally Regulated Genes

Molecular and Cellular Biology ◽

10.1128/mcb.21.15.5242-5255.2001 ◽

2001 ◽

Vol 21 (15) ◽

pp. 5242-5255 ◽

Cited By ~ 21

Author(s):

Byung Soo Gim ◽

Jin Mo Park ◽

Jeong Ho Yoon ◽

Changwon Kang ◽

Young-Joon Kim

Keyword(s):

Cell Proliferation ◽

Drosophila Melanogaster ◽

Transcriptional Activation ◽

Larval Instar ◽

Developmentally Regulated ◽

The Third ◽

Reverse Transcription Pcr ◽

Evolutionarily Conserved ◽

Elevated Expression

ABSTRACT Mediator is the evolutionarily conserved coactivator required for the integration and recruitment of diverse regulatory signals to basal transcription machinery. To elucidate the functions of metazoan Mediator, we isolated Drosophila melanogaster Med6mutants. dMed6 is essential for viability and/or proliferation of most cells. dMed6 mutants failed to pupate and died in the third larval instar with severe proliferation defects in imaginal discs and other larval mitotic cells. cDNA microarray, quantitative reverse transcription-PCR, and in situ expression analyses of developmentally regulated genes indMed6 mutants showed that transcriptional activation of many, but not all, genes was affected. Among the genes found to be affected were some that play a role in cell proliferation and metabolism. Therefore, dMed6 is required in most cells for transcriptional regulation of many genes important for diverse aspects of Drosophila development.

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The Hippo Signaling Network and Its Biological Functions

Annual Review of Genetics ◽

10.1146/annurev-genet-120417-031621 ◽

2018 ◽

Vol 52 (1) ◽

pp. 65-87 ◽

Cited By ~ 91

Author(s):

Jyoti R. Misra ◽

Kenneth D. Irvine

Keyword(s):

Cell Proliferation ◽

Cell Fate ◽

Growth Control ◽

Cell Junctions ◽

Hippo Signaling ◽

Transcriptional Coactivator ◽

Biological Functions ◽

Evolutionarily Conserved ◽

Control Organ ◽

Transcriptional Coactivator Proteins

Hippo signaling is an evolutionarily conserved network that has a central role in regulating cell proliferation and cell fate to control organ growth and regeneration. It promotes activation of the LATS kinases, which control gene expression by inhibiting the activity of the transcriptional coactivator proteins YAP and TAZ in mammals and Yorkie in Drosophila. Diverse upstream inputs, including both biochemical cues and biomechanical cues, regulate Hippo signaling and enable it to have a key role as a sensor of cells’ physical environment and an integrator of growth control signals. Several components of this pathway localize to cell–cell junctions and contribute to regulation of Hippo signaling by cell polarity, cell contacts, and the cytoskeleton. Downregulation of Hippo signaling promotes uncontrolled cell proliferation, impairs differentiation, and is associated with cancer. We review the current understanding of Hippo signaling and highlight progress in the elucidation of its regulatory mechanisms and biological functions.

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NH2 terminus of serum and glucocorticoid-regulated kinase 1 binds to phosphoinositides and is essential for isoform-specific physiological functions

AJP Renal Physiology ◽

10.1152/ajprenal.00027.2007 ◽

2007 ◽

Vol 292 (6) ◽

pp. F1741-F1750 ◽

Cited By ~ 28

Author(s):

Alan C. Pao ◽

James A. McCormick ◽

Hongyan Li ◽

John Siu ◽

Cedric Govaerts ◽

...

Keyword(s):

Cell Proliferation ◽

Kinase Activity ◽

Regulatory Protein ◽

Forkhead Transcription Factor ◽

Cellular Processes ◽

Cellular Compartments ◽

Stimulation Of

Serum and glucocorticoid regulated kinase 1 (SGK1) has been identified as a key regulatory protein that controls a diverse set of cellular processes including sodium (Na+) homeostasis, osmoregulation, cell survival, and cell proliferation. Two other SGK isoforms, SGK2 and SGK3, have been identified, which differ most markedly from SGK1 in their NH2-terminal domains. We found that SGK1 and SGK3 are potent stimulators of epithelial Na+ channel (ENaC)-dependent Na+ transport, while SGK2, which has a short NH2 terminus, is a weak stimulator of ENaC. Further characterization of the role of the SGK1 NH2 terminus revealed that its deletion does not affect in vitro kinase activity but profoundly limits the ability of SGK1 either to stimulate ENaC-dependent Na+ transport or inhibit Forkhead-dependent gene transcription. The NH2 terminus of SGK1, which shares sequence homology with the phosphoinositide 3-phosphate [PI( 3 )P] binding domain of SGK3, binds phosphoinositides in protein lipid overlay assays, interacting specifically with PI( 3 )P, PI( 4 )P, and PI( 5 )P, but not with PI( 3 , 4 , 5 )P3. Moreover, a point mutation that reduces phosphoinositide binding to the NH2 terminus also reduces SGK1 effects on Na+ transport and Forkhead activity. These data suggest that the NH2 terminus, although not required for PI 3-kinase-dependent modulation of SGK1 catalytic activity, is required for multiple SGK1 functions, including stimulation of ENaC and inhibition of the proapoptotic Forkhead transcription factor. Together, these observations support the idea that the NH2-terminal domain acts downstream of PI 3-kinase-dependent activation to target the kinase to specific cellular compartments and/or substrates, possibly through its interactions with a subset of phosphoinositides.

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p14ARF Activates a Tip60-Dependent and p53-Independent ATM/ATR/CHK Pathway in Response to Genotoxic Stress

Molecular and Cellular Biology ◽

10.1128/mcb.02240-05 ◽

2006 ◽

Vol 26 (11) ◽

pp. 4339-4350 ◽

Cited By ~ 72

Author(s):

Béatrice Eymin ◽

Paule Claverie ◽

Caroline Salon ◽

Camille Leduc ◽

Edwige Col ◽

...

Keyword(s):

Alkylating Agents ◽

Growth Control ◽

Genotoxic Stress ◽

Lung Carcinogenesis ◽

Binding Partner ◽

Dna Damage Signaling ◽

Cycle Arrest ◽

A Cell ◽

Tumor Suppressive Function ◽

Cell Growth Control

ABSTRACT p14ARF is a tumor suppressor that controls a well-described p53/Mdm2-dependent checkpoint in response to oncogenic signals. Here, new insights into the tumor-suppressive function of p14ARF are provided. We previously showed that p14ARF can induce a p53-independent G2 cell cycle arrest. In this study, we demonstrate that the activation of ATM/ATR/CHK signaling pathways contributes to this G2 checkpoint and highlight the interrelated roles of p14ARF and the Tip60 protein in the initiation of this DNA damage-signaling cascade. We show that Tip60 is a new direct p14ARF binding partner and that its expression is upregulated and required for ATM/CHK2 activation in response to p14ARF. Strikingly, both p14ARF and Tip60 products accumulate following a cell treatment with alkylating agents and are absolutely required for ATM/CHK2 activation in this setting. Moreover, and consistent with p14ARF being a determinant of CHK2 phosphorylation in lung carcinogenesis, a strong correlation between p14ARF and phospho-CHK2 (Thr68) protein expression is observed in human lung tumors (P < 0.00006). Overall, these data point to a novel regulatory pathway that mediates the p53-independent negative-cell-growth control of p14ARF. Inactivation of this pathway is likely to contribute to lung carcinogenesis.

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Identification and Partial Characterization of a Dynamin-Like Protein, EhDLP1, from the Protist Parasite Entamoeba histolytica

Eukaryotic Cell ◽

10.1128/ec.00214-09 ◽

2009 ◽

Vol 9 (1) ◽

pp. 215-223 ◽

Cited By ~ 8

Author(s):

Ruchi Jain ◽

Shiteshu Shrimal ◽

Sudha Bhattacharya ◽

Alok Bhattacharya

Keyword(s):

Entamoeba Histolytica ◽

Nuclear Membrane ◽

Mitochondrial Fission ◽

Lipid Binding ◽

Gene Encoding ◽

Cellular Processes ◽

Gtp Binding ◽

Evolutionarily Conserved ◽

Associated Function

ABSTRACT The dynamin superfamily of proteins includes a large repertoire of evolutionarily conserved GTPases that interact with different subcellular organelle membranes in eukaryotes. Dynamins are thought to participate in a number of cellular processes involving membrane remodeling and scission. Dynamin-like proteins (DLPs) form a subfamily of this vast class and play important roles in cellular processes, such as mitochondrial fission, cytokinesis, and endocytosis. In the present study, a gene encoding a dynamin-like protein (EhDLP1) from the protist parasite Entamoeba histolytica was identified and the protein was partially characterized using a combination of in silico, biochemical, and imaging methods. The protein was capable of GTP binding and hydrolysis, lipid binding, and oligomerization. Immunofluorescence studies showed the protein to be associated with the nuclear membrane. A mutant of EhDLP1 lacking GTP binding and hydrolyzing activities did not associate with the nuclear membrane. The results suggest a nucleus-associated function for EhDLP1.

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