Isolation of Two Novel Human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13-21 and 2q22

Thiesen, Signe; Kübart, Sabine; Ropers, Hans Hilger; Nothwang, Hans Gerd

doi:10.1006/bbrc.2000.2925

Cited by 30 publications

(25 citation statements)

References 14 publications

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“…It may modulate many cellular processes that are initiated by G-protein signalization [25]. In our study the gene had higher expression in the group without recurrence.…”

Section: Discussionsupporting

confidence: 44%

Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results

Mareš¹,

Szakácsová²,

Soukup³

et al. 2013

neo

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The aim of the study was to define specific genetic profile in Ta and T1 urinary bladder carcinoma patients with and without recurrence by gene expression microarrays. Eleven patients with the time to recurrence shorter than one year (patients with recurrence) and 11 patients with time to recurrence longer than 4 years (patients without recurrence) were enrolled.Data from microarrays were subjected to a panel of statistical analyses to identify bladder cancer recurrence-associated gene signatures. Initial screening using the GeneSpring and Bioconductor software tools revealed a putative set 47 genes differing in gene expression in both groups. After the validation, 33 genes manifested significant differences between both groups. The significant expression was observed in the group of patients without recurrence by 30 genes of which the highest differences were detected by ANXA1, ARHGEF4, FLJ32252, GNE, NINJ1, PRICKLE1, PSAT1, RNASE1, SPTAN1, SYNGR1, TNFSF15, TSPAN1, and WDR34. These genes code for signal transduction, vascular remodeling and vascular endothelial growth inhibition mainly. In the group with recurrence, 3 genes had significant differences, the highest differences were identified by two genes (PLOD2 and WDR72).Loci of genes with significant changes of gene expression were located on characteristic chromosomes for bladder cancer: 7 loci on chromosome 9, 8 loci on chromosomes 1, 2, 3, 12, 14, 15, 16, and 22. We have selected and validated 15 genes that are differentially expressed in superficial bladder cancer. We hope that this cohort of genes will serve as a promising pool of candidate biomarkers for early stage bladder cancer. Our results indicate that it may be possible to identify patients with a low and high risk of disease recurrence at an early stage using a molecular profile. Key words: bladder cancer, non-muscle invasive urothelial tumors, gene expression microarraysBladder cancer (BC) is the sixth most frequent solid tumor in men and thirteenth in women in Czech Republic with 1827 and 650 new cases in 2005, respectively [1] and 375.000 new cases and 145.000 deaths worldwide annually [2]. Urothelial carcinoma (UC) is a heterogenous neoplasm manifesting either non-muscle invasive bladder cancer (NMIBC) -Ta, T1 and Tis by approximatelly 75 % newly diagnosed cases or muscle invasive (T2-T4) and metastatic tumor (25 %) [3,4]. After initial treatment of NMIBC by transurethral resection (TURB) up to 80 % of patients develop recurrences. From 10 % to 15 % of them progress to muscle invasive cancer [5,6]. For treatment and follow up of patients it is crucial to predict the recurrence and progression potential of non-muscle invasive bladder cancer. Therefore new methods are engaged to identify new prognostic markers based on the molecular nature of the tumor development and recurrence [7,8].The objective of our study was to identify the genes differing in gene expression in tumors with and without recurrence. Among the genes it might be determined a gene or several genes serving as factors for furt...

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“…It may modulate many cellular processes that are initiated by G-protein signalization [25]. In our study the gene had higher expression in the group without recurrence.…”

Section: Discussionsupporting

confidence: 44%

Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results

Mareš¹,

Szakácsová²,

Soukup³

et al. 2013

neo

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“…ARHGEF3 encodes the rho guanine-nucleotide exchange factor 3 (RhoGEF3), which activates RhoGTPases, which play an important role in the regulation of cell morphology, cell aggregation, cytoskeletal rearrangements, and transcriptional activation. 77,78 TAOK1 encodes the TAO kinase 1 peptide (hTAOK1, also known as MARKK or PSK2), a microtubule affinity-regulating kinase important in regulation of mitotic progression, chromosome congression, and checkpoint-induced anaphase delay. 79 The 7q22.3 locus discovered by Soranzo et al 68 explains 1.5% of the variance in MPV attributable to genetic factors, and the 3 QTL identified by together account for only 4% to 5% of the variance in MPV.…”

Section: Gwasmentioning

confidence: 99%

The genetics of normal platelet reactivity

Kunicki

Nugent

2010

Blood

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Genetic and environmental factors contribute to a substantial variation in platelet function seen among normal persons. Candidate gene association studies represent a valiant effort to define the genetic component in an era where genetic tools were limited, but the single nucleotide polymorphisms identified in those studies need to be validated by more objective, comprehensive approaches, such as genome-wide association studies (GWASs) of quantitative functional traits in much larger cohorts of more carefully selected normal subjects. During the past year, platelet count and mean platelet volume, which indirectly affect platelet function, were the subjects of GWAS. IntroductionInterindividual platelet responsiveness to a variety of agonists is highly variable, as documented in several studies of large cohorts of normal persons. [1][2][3][4][5][6][7][8][9][10][11][12] At the same time, these and other studies of siblings, twins, and families with a history of coronary artery disease (CAD) have documented that intraindividual responsiveness is highly reproducible over time, regardless of the agonist tested or the chosen method of assessment. These findings strongly suggest that there is a high level of heritability of platelet function, and this has prompted numerous attempts to define the genetic basis for platelet function variability. A summary of platelet functionTo fully appreciate the gene association studies, it is necessary to briefly summarize key aspects of platelet function and establish a molecular and physiologic basis for the selection of genes to study.When a blood vessel is damaged, circulating platelets interact with components of the extracellular matrix, particularly collagen, and a complex series of receptor-ligand interactions ensues that ultimately leads to the formation of a stable platelet plug or thrombus. This process is a continuum of at least 3 phases that we can describe as initiation, extension, and consolidation, each of which entails the cooperation of a different group of receptors.In the initiation phase, plasma von Willebrand factor (VWF) binds to collagen via its A3 domain and becomes structurally altered such that its A1 domain then binds to the platelet membrane receptor glycoprotein Ib-IX-V complex (GPIb complex). It is the GPIb␣ or larger subunit of GPIb that makes direct contact with VWF. This association is a requisite step in the adhesion of platelets to exposed thrombogenic surfaces at sites of vessel wall injury or in regions of atherosclerotic plaque rupture. Concurrently, a more stable platelet monolayer is formed on the collagen surface mediated predominantly by the platelet-specific receptor glycoprotein VI (GPVI) and platelet integrin ␣ 2 ␤ 1 .The engagement of these receptors enhances platelet activation leading to the extension phase, mediated largely by the conversion of prothrombin to thrombin at the activated platelet surface and the secretion of active compounds from platelet granules (␣-granules and ␦-granules), which can further stimulate platelets. One of...

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“…17 ; here called ASEF). This isoform contains sequences on the N-terminal side of the ABR domain that are distinct from those encoded in the gene that was originally cloned 8 .We therefore used this predominant isoform throughout the experiments below as full-length ASEF (residues 1-690; see Supplementary Methods.online).…”

Section: Asef Is Autoinhibited By the Sh3 Domainmentioning

confidence: 99%

Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

Mitin

Betts

Yohe

et al. 2007

Nat Struct Mol Biol

116

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Autoinhibition of the Rho guanine nucleotide exchange factor ASEF is relieved by interaction with the APC tumor suppressor. Here we show that binding of the armadillo repeats of APC to a 'core APC-binding' (CAB) motif within ASEF, or truncation of the SH3 domain of ASEF, relieves autoinhibition, allowing the specific activation of CDC42. Structural determination of autoinhibited ASEF reveals that the SH3 domain forms an extensive interface with the catalytic DH and PH domains to obstruct binding and activation of CDC42, and the CAB motif is positioned adjacent to the SH3 domain to facilitate activation by APC. In colorectal cancer cell lines, full-length, but not truncated, APC activates CDC42 in an ASEF-dependent manner to suppress anchorage-independent growth. We therefore propose a model in which ASEF acts as a tumor suppressor when activated by APC and inactivation of ASEF by mutation or APC truncation promotes tumorigenesis.The adenomatous polyposis coli (APC) protein is a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of β-catenin 1 . The majority of colorectal cancers (CRCs) harbor C-terminally truncated forms of APC that retain the Nterminal coiled-coil domain and the highly conserved armadillo repeat region (APC Arm ) 2 and are unable to regulate the degradation of β-catenin 3 . Recent studies suggest that APC regulates cytoskeletal dynamics to influence cellular migration, cell division, polarization and adhesion, and it seems increasingly likely that deregulated cytoskeletal dynamics, together with enhancement of transcription by β-catenin, potentiate tumor formation and progression upon APC truncation. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptAPC may regulate cytoskeletal networks by binding to microtubules and to proteins implicated in reorganization of the actin cytoskeleton, such as the Rho effectors mDia and IQGAP1 and the Rho guanine nucleotide exchange factor (RhoGEF) 'APC-stimulated guanine nucleotide exchange factor' (ASEF, also called ARHGEF4) 4 . ASEF is a Dbl-family GEF that contains an Src-homology-3 (SH3) domain followed by the Dbl-homology (DH) and pleckstrinhomology (PH) domains characteristic of Dbl-family GEFs that specifically activate members of the Rho family of GTPases. DH and PH domains in Dbl proteins catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors 5 . ASEF is homologous to the Dbl proteins collybistin (also called PEM2) and SPATA13 (also called ASEF2), both of which have been shown to activate specifically CDC42 and not other Rhofamily GTPases 6,7 .Previous data suggest that ASEF exists in an autoinhibited form and is activated upon binding of APC Arm to the region termed the APC-binding region (ABR) 8 . Binding of APC Arm to the ABR stimulates activation of the Rho GTPase RAC1 by ASEF. Furthermore, truncation of the ABR is sufficient to relieve autoinhibition, rendering ASEF constitutively active. In addition, truncated, but not wild-...

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Isolation of Two Novel Human RhoGEFs, ARHGEF3 and ARHGEF4, in 3p13-21 and 2q22

Cited by 30 publications

References 14 publications

Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results

Prediction of recurrence in low and intermediate risk non-muscle invasive bladder cancer by real-time quantitative PCR analysis: cDNA microarray results

The genetics of normal platelet reactivity

Release of autoinhibition of ASEF by APC leads to CDC42 activation and tumor suppression

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