Genomes and Genes
Gene Symbol: PREX1
Description: phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1
Alias: P-REX1, phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, PIP3 dependent Rac exchange factor 1, ptdIns(3,4,5)-dependent Rac exchanger 1
- Adame García S, Cervantes Villagrana R, Orduña Castillo L, Del Rio J, Gutkind J, Reyes Cruz G, et al. cAMP-dependent activation of the Rac guanine exchange factor P-REX1 by type I protein kinase A (PKA) regulatory subunits. J Biol Chem. 2019;294:2232-2246 pubmed publisher..We conclude that PKA's regulatory subunits are cAMP-dependent signal transducers. ..
- Kazanietz M, Barrio Real L, Casado Medrano V, Baker M, Lopez Haber C. The P-Rex1/Rac signaling pathway as a point of convergence for HER/ErbB receptor and GPCR responses. Small Gtpases. 2018;9:297-303 pubmed publisher..We propose a model in which P-Rex1 acts as a crucial node for the integration of upstream inputs from HER/ErbB receptors and CXCR4 in luminal breast cancer cells. ..
- Cervantes Villagrana R, Adame García S, García Jiménez I, Color Aparicio V, Beltrán Navarro Y, König G, et al. Gβγ signaling to the chemotactic effector P-REX1 and mammalian cell migration is directly regulated by Gαq and Gα13 proteins. J Biol Chem. 2019;294:531-546 pubmed publisher..We conclude that a coordinated mechanism prioritizes Gαq- and Gα13-mediated signaling to Rho over a Gβγ-dependent Rac pathway, attributed to heterotrimeric Gi proteins. ..
- Ebi H, Costa C, Faber A, Nishtala M, Kotani H, Juric D, et al. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc Natl Acad Sci U S A. 2013;110:21124-9 pubmed publisher..In addition, P-Rex1 may serve as a biomarker to predict response to single-agent PI3K inhibitors within this subset of breast cancers. ..
- Dinkel B, Kremer K, Rollins M, Medlyn M, Hedin K. GRK2 mediates TCR-induced transactivation of CXCR4 and TCR-CXCR4 complex formation that drives PI3Kγ/PREX1 signaling and T cell cytokine secretion. J Biol Chem. 2018;293:14022-14039 pubmed publisher..TCR to signal via CXCR4 to activate a phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein (PREX1)-dependent signaling pathway that drives robust cytokine secretion by T cells...
- Welch H. Regulation and function of P-Rex family Rac-GEFs. Small Gtpases. 2015;6:49-70 pubmed publisher..Both GEFs promote tumor growth or metastasis. This review critically evaluates the P-Rex literature and tools available and highlights exciting recent developments and open questions. ..
- Dirat B, Ader I, Golzio M, Massa F, Mettouchi A, Laurent K, et al. Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells. Mol Cancer Ther. 2015;14:586-96 pubmed publisher..These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer. ..
- Chattopadhyay S, Thomsen H, da Silva Filho M, Weinhold N, Hoffmann P, Nothen M, et al. Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study. Mol Med. 2018;24:30 pubmed publisher..Intronic-PREX1 (20q13...
- Zhang C, Elkahloun A, Liao H, Delaney S, Saber B, Morrow B, et al. Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells. Mol Cancer Ther. 2011;10:1137-48 pubmed publisher..expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and ..
- Rosmaninho P, Mükusch S, Piscopo V, Teixeira V, Raposo A, Warta R, et al. Zeb1 potentiates genome-wide gene transcription with Lef1 to promote glioblastoma cell invasion. EMBO J. 2018;37: pubmed publisher..are predicted mediators of tumor cell migration and invasion, including the guanine nucleotide exchange factor Prex1, whose elevated expression is predictive of shorter glioblastoma patient survival...
- Pan D, Amison R, Riffo Vasquez Y, Spina D, Cleary S, Wakelam M, et al. P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation. Blood. 2015;125:1146-58 pubmed publisher..Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment. ..
- Liang Q, Cheng N, Zhang G, Liang Y, Qian F, Wu D, et al. Identification of P-Rex1 as an anti-inflammatory and anti-fibrogenic target for pulmonary fibrosis. Sci Rep. 2016;6:25785 pubmed publisher..These findings identify P-Rex1 as a novel player of PF, suggesting that targeting P-Rex1 may simultaneously block the inflammatory and fibrogenic processes of PF. ..
- Lopez Haber C, Barrio Real L, Casado Medrano V, Kazanietz M. Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α. Mol Cell Biol. 2016;36:2011-26 pubmed publisher..Our results uncovered a novel function for ErbB3 in enhancing breast cancer cell motility and sensitization of the P-Rex1/Rac1 pathway through HIF-1α-mediated transcriptional induction of CXCR4. ..
- Marei H, Carpy A, Woroniuk A, Vennin C, White G, Timpson P, et al. Differential Rac1 signalling by guanine nucleotide exchange factors implicates FLII in regulating Rac1-driven cell migration. Nat Commun. 2016;7:10664 pubmed publisher..In particular, we demonstrate that P-Rex1 stimulates migration through enhancing the interaction between Rac1 and the actin-remodelling protein flightless-1 homologue, to modulate cell contraction in a RhoA-ROCK-independent manner. ..
- Jin S, Lee H, Kim E, Ha J, Kim Y, Bae S. Reactive oxygen species and PI3K/Akt signaling in cancer. Free Radic Biol Med. 2014;75 Suppl 1:S34-5 pubmed publisher..Given these results, we suggest that IGF-1 induces ROS generation through the PI3K/Akt/ mTOR2/NADPH oxidase signaling axis. ..
- Graziano B, Gong D, Anderson K, Pipathsouk A, Goldberg A, Weiner O. A module for Rac temporal signal integration revealed with optogenetics. J Cell Biol. 2017;216:2515-2531 pubmed publisher..This circuit is masked by feedback and redundancy when chemoattractant is used as the input, highlighting the value of probing signaling networks at intermediate nodes to deconvolve complex signaling cascades. ..
- Pan D, Barber M, Hornigold K, Baker M, Toth J, Oxley D, et al. Norbin Stimulates the Catalytic Activity and Plasma Membrane Localization of the Guanine-Nucleotide Exchange Factor P-Rex1. J Biol Chem. 2016;291:6359-75 pubmed publisher..In summary, we have identified a novel mechanism of P-Rex1 regulation through the GPCR-adaptor protein Norbin, a direct P-Rex1 interacting protein that promotes the Rac-GEF activity and membrane localization of P-Rex1. ..
- HernÃ¡ndez GarcÃa R, Iruela Arispe M, Reyes Cruz G, VÃ¡zquez Prado J. Endothelial RhoGEFs: A systematic analysis of their expression profiles in VEGF-stimulated and tumor endothelial cells. Vascul Pharmacol. 2015;74:60-72 pubmed publisher..In summary, our results provide a detailed assessment of RhoGEFs expression profiles in the endothelium and set the basis to systematically address their regulation in vascular signaling. ..
- Marei H, Carpy A, Macek B, Malliri A. Proteomic analysis of Rac1 signaling regulation by guanine nucleotide exchange factors. Cell Cycle. 2016;15:1961-74 pubmed publisher..In light of this data, we also provide additional insights into known and novel signaling cascades that might account for the GEF-mediated Rac1-driven cellular effects. ..
- Ryan M, Finn A, Pedone K, Thomas N, Der C, Cox A. ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma. Mol Cancer Res. 2016;14:1009-1018 pubmedRecently, we identified that PREX1 overexpression is critical for metastatic but not tumorigenic growth in a mouse model of NRAS-driven melanoma...
- Vazquez Prado J, Bracho Valdés I, Cervantes Villagrana R, Reyes Cruz G. G?? Pathways in Cell Polarity and Migration Linked to Oncogenic GPCR Signaling: Potential Relevance in Tumor Microenvironment. Mol Pharmacol. 2016;90:573-586 pubmed..Here we discuss emerging paradigms of G?? signaling in cancer, which are essential for chemotactic cell migration and represent novel opportunities to develop pathway-specific pharmacologic treatments. ..
- Xia J, Qi X, Wu Y, Zhu B, Xu L, Zhang L, et al. Genome-wide association study identifies loci and candidate genes for meat quality traits in Simmental beef cattle. Mamm Genome. 2016;27:246-55 pubmed publisher..have been reported previously, including TMEM236, SORL1, TRDN, S100A10, AP2S1, KCTD16, LOC506594, DHX15, LAMA4, PREX1, and BRINP3...
- Xue R, Lynes M, Dreyfuss J, Shamsi F, Schulz T, Zhang H, et al. Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes. Nat Med. 2015;21:760-8 pubmed publisher..Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes ..
- Levy D, Larson M, Benjamin E, Newton Cheh C, Wang T, Hwang S, et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet. 2007;8 Suppl 1:S3 pubmed..Additional studies are needed to replicate any associations identified in these analyses. ..
- Goel H, Pursell B, Shultz L, Greiner D, Brekken R, Vander Kooi C, et al. P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer. Cell Rep. 2016;14:2193-2208 pubmed publisher..Combining the use of available VEGF/VEGFR-targeted therapies with P-Rex1 or Rac1 inhibition should improve the efficacy of these therapies significantly. ..
- Kim E, Yun S, Ha J, Kim Y, Jin I, Yun J, et al. Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis. Oncogene. 2011;30:2954-63 pubmed publisher..Given these results, we suggest that selective activation of Akt1 through mTORC2 and P-Rex1 regulates cancer cell migration, invasion and metastasis. ..
- Nie B, Cheng N, Dinauer M, Ye R. Characterization of P-Rex1 for its role in fMet-Leu-Phe-induced superoxide production in reconstituted COS(phox) cells. Cell Signal. 2010;22:770-82 pubmed publisher..These results demonstrate that in COS(phox) cells, P-Rex1 is a critical component for FPR1-mediated signaling leading to NADPH oxidase activation, and there is a crosstalk between the P-Rex1-Rac pathway and Akt in superoxide generation. ..
- Carretero Ortega J, Walsh C, Hernández García R, Reyes Cruz G, Brown J, Vazquez Prado J. Phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex-1), a guanine nucleotide exchange factor for Rac, mediates angiogenic responses to stromal cell-derived factor-1/chemokine stromal cell derived factor-1 (SDF-1/CXCL-12) linked t. Mol Pharmacol. 2010;77:435-42 pubmed publisher..We conclude that P-Rex1 is a key element in SDF-1-induced angiogenic responses and a potential target for therapeutic intervention. ..
- Wang T, Yu H, Hughes N, Liu B, Kendirli A, Klein K, et al. Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal Interactions with Oncogenic Ras. Cell. 2017;168:890-903.e15 pubmed publisher..pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling...
- Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, et al. Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet. 2011;43:459-63 pubmed publisher..This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease. ..
- Li J, Chai A, Wang L, Ma Y, Wu Z, Yu H, et al. Synaptic P-Rex1 signaling regulates hippocampal long-term depression and autism-like social behavior. Proc Natl Acad Sci U S A. 2015;112:E6964-72 pubmed publisher..Together, our findings suggest a vital role of P-Rex1 signaling in CA1 LTD that is critical for social behavior and cognitive function and offer new insight into the etiology of ASDs. ..
- Qian F, Le Breton G, Chen J, Deng J, Christman J, Wu D, et al. Role for the guanine nucleotide exchange factor phosphatidylinositol-3,4,5-trisphosphate-dependent rac exchanger 1 in platelet secretion and aggregation. Arterioscler Thromb Vasc Biol. 2012;32:768-77 pubmed publisher..These results demonstrate for the first time the presence of P-Rex1 in platelets as well as its role in platelet secretion and aggregation induced by low-dose agonists for GPCR and by collagen. ..
- Campbell A, Lawn S, McGarry L, Welch H, Ozanne B, Norman J. P-Rex1 cooperates with PDGFR? to drive cellular migration in 3D microenvironments. PLoS ONE. 2013;8:e53982 pubmed publisher..These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes. ..
- Fossey S, Mychaleckyj J, Pendleton J, Snyder J, Bensen J, Hirakawa S, et al. A high-resolution 6.0-megabase transcript map of the type 2 diabetes susceptibility region on human chromosome 20. Genomics. 2001;76:45-57 pubmed..The combination of the BAC transcript map, YAC-to-BAC scaffold, and reference Human Genome Project sequence provides a powerful integrated resource for future genomic analysis of this region. ..
- Zhao T, Nalbant P, Hoshino M, Dong X, Wu D, Bokoch G. Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function. J Leukoc Biol. 2007;81:1127-36 pubmed
- Mayeenuddin L, Garrison J. Phosphorylation of P-Rex1 by the cyclic AMP-dependent protein kinase inhibits the phosphatidylinositiol (3,4,5)-trisphosphate and Gbetagamma-mediated regulation of its activity. J Biol Chem. 2006;281:1921-8 pubmed..Treatment of the cells with S(p)-cAMPS also reduced the levels of GTP-bound Rac. These results outline a novel mechanism for G(s)-linked receptors to regulate the function of P-Rex1 and inhibit its function in cells. ..
- Lopez Haber C, Kazanietz M. Cucurbitacin I inhibits Rac1 activation in breast cancer cells by a reactive oxygen species-mediated mechanism and independently of Janus tyrosine kinase 2 and P-Rex1. Mol Pharmacol. 2013;83:1141-54 pubmed publisher..Moreover, they established that the inhibitory effect of cucurbitacin I on Rac1 activity involves the alteration of the balance between Rho and Rac. ..
- ChÃ¡vez Vargas L, Adame GarcÃa S, Cervantes Villagrana R, Castillo Kauil A, Bruystens J, Fukuhara S, et al. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING. J Biol Chem. 2016;291:6182-99 pubmed publisher..This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. ..
- Waters J, Astle M, Ooms L, Balamatsias D, Gurung R, Mitchell C. P-Rex1 - a multidomain protein that regulates neurite differentiation. J Cell Sci. 2008;121:2892-903 pubmed publisher..This study has identified P-Rex1 as a Rac3-GEF in neuronal cells that localises to, and regulates, actin cytoskeletal dynamics at the axonal growth cone to in turn regulate neurite differentiation. ..
- Barber M, Hendrickx A, Beullens M, Ceulemans H, Oxley D, Thelen S, et al. The guanine-nucleotide-exchange factor P-Rex1 is activated by protein phosphatase 1?. Biochem J. 2012;443:173-83 pubmed publisher..In summary, we have identified a novel mechanism for direct activation of P-Rex1 through PP1?-dependent dephosphorylation. ..
- Wang J, Hirose H, Du G, Chong K, Kiyohara E, Witz I, et al. P-REX1 amplification promotes progression of cutaneous melanoma via the PAK1/P38/MMP-2 pathway. Cancer Lett. 2017;407:66-75 pubmed publisher..These results suggest P-REX1 plays an important role in tumor progression and a potential theranostic target. ..
- Srijakotre N, Man J, Ooms L, Lucato C, Ellisdon A, Mitchell C. P-Rex1 and P-Rex2 RacGEFs and cancer. Biochem Soc Trans. 2017;45:963-77 pubmed publisher..Emerging clinical data predict that changes in expression or mutation of P-Rex1 and P-Rex2 may lead to changes in tumour outcome, particularly in breast cancer and melanoma. ..
- Lucato C, Halls M, Ooms L, Liu H, Mitchell C, Whisstock J, et al. The Phosphatidylinositol (3,4,5)-Trisphosphate-dependent Rac Exchanger 1Â·Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1Â·Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells. J Biol Chem. 2015;290:20827-40 pubmed publisher
- Montero J, Seoane S, GarcÃa Alonso S, Pandiella A. Multisite phosphorylation of P-Rex1 by protein kinase C. Oncotarget. 2016;7:77937-77949 pubmed publisher..We suggest that control of P-Rex1 activity depends on a highly dynamic interplay among distinct signalling routes and its multisite phosphorylation is controlled by the action of different kinases. ..
- Luca G, Haba Rubio J, Dauvilliers Y, Lammers G, Overeem S, Donjacour C, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res. 2013;22:482-95 pubmed publisher..Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms. ..
- Barrio Real L, Benedetti L, Engel N, Tu Y, Cho S, Sukumar S, et al. Subtype-specific overexpression of the Rac-GEF P-REX1 in breast cancer is associated with promoter hypomethylation. Breast Cancer Res. 2014;16:441 pubmed publisher..basis of P-REX1 overexpression in breast cancer, in this study we focused on the analysis of methylation of the PREX1 gene promoter...
- Barrows D, He J, Parsons R. PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs). J Biol Chem. 2016;291:20042-54 pubmed publisher..b>PREX1 and PREX2 GEF activity is activated by the second messengers PIP3 and G??, and further regulation of PREX GEF ..
- Lewis J, Palmer N, Ellington J, Divers J, Ng M, Lu L, et al. Analysis of candidate genes on chromosome 20q12-13.1 reveals evidence for BMI mediated association of PREX1 with type 2 diabetes in European Americans. Genomics. 2010;96:211-9 pubmed publisher..00090-0.045). SNPs near PREX1 were also associated in the second case-control population (P(a)=0.017-0.042)...
- Ledezma Sánchez B, García Regalado A, Guzmán Hernández M, Vazquez Prado J. Sphingosine-1-phosphate receptor S1P1 is regulated by direct interactions with P-Rex1, a Rac guanine nucleotide exchange factor. Biochem Biophys Res Commun. 2010;391:1647-52 pubmed publisher..We conclude that S1P(1) signaling linked to cell migration is facilitated by a functional interaction with P-Rex1 via a mechanism that involves the maintenance of S1P(1) receptors at the cell membrane. ..
- Gont A, Daneshmand M, Woulfe J, Lavictoire S, Lorimer I. PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion. Oncotarget. 2017;8:8559-8573 pubmed publisher..b>PREX1 is a Rac guanine nucleotide exchange factor that is synergistically activated by binding of G protein Î±Î³ ..
- Liu H, Ooms L, Srijakotre N, Man J, Vieusseux J, Waters J, et al. PtdIns(3,4,5)P3-dependent Rac Exchanger 1 (PREX1) Rac-Guanine Nucleotide Exchange Factor (GEF) Activity Promotes Breast Cancer Cell Proliferation and Tumor Growth via Activation of Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Signaling. J Biol Chem. 2016;291:17258-70 pubmed publisherPtdIns(3,4,5)P3-dependent Rac exchanger 1 (PREX1) is a Rac-guanine nucleotide exchange factor (GEF) overexpressed in a significant proportion of human breast cancers that integrates signals from upstream ErbB2/3 and CXCR4 membrane ..
- Cash J, Davis E, Tesmer J. Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3. Structure. 2016;24:730-740 pubmed publisher..Collectively, this study provides important molecular insights into P-Rex1 regulation and tools for targeting the PIP3-binding pocket of P-Rex1 with a new generation of cancer chemotherapeutic agents. ..
- Kremer K, Dinkel B, Sterner R, Osborne D, Jevremovic D, Hedin K. TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL. Blood. 2017;130:982-994 pubmed publisher..TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1-signaling pathway that stabilizes interleukin-2(IL-2), IL-4, and IL-10 messenger ..
- Wong C, Wuriyanghan H, Xie Y, Lin M, Abel P, Tu Y. Epigenetic regulation of phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 gene expression in prostate cancer cells. J Biol Chem. 2011;286:25813-22 pubmed publisher..Disassociation of HDACs from Sp1 on the P-Rex1 promoter may contribute to aberrant up-regulation of P-Rex1 in cancer. ..
- Barrio Real L, Wertheimer E, Garg R, Abba M, Kazanietz M. Characterization of a P-Rex1 gene signature in breast cancer cells. Oncotarget. 2016;7:51335-51348 pubmed publisher..Notably, there is a significant association in the expression of P-Rex1 and MMP10 in human luminal breast cancer, and their co-expression is indicative of poor prognosis. ..
- Bento J, Palmer N, Zhong M, Roh B, Lewis J, Wing M, et al. Heterogeneity in gene loci associated with type 2 diabetes on human chromosome 20q13.1. Genomics. 2008;92:226-34 pubmed publisher..22), ELMO2 (engulfment and cell motility 2), SLC13A3 (sodium-dependent dicarboxylate transporter member 3), and PREX1 (phosphatidylinositol 3,4,5-triphosphate-dependent RAC exchanger 1)...