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Youtao Liu, Jesus Lacal, Douwe M Veltman, Fabrizia Fusetti, Peter J M van Haastert, Richard A Firtel, Arjan Kortholt
Chemotaxis, or directional movement toward extracellular chemical gradients, is an important property of cells that is mediated through G-protein-coupled receptors (GPCRs). Although many chemotaxis pathways downstream of Gβγ have been identified, few Gα effectors are known. Gα effectors are of particular importance because they allow the cell to distinguish signals downstream of distinct chemoattractant GPCRs. Here we identify GflB, a Gα2 binding partner that directly couples the Dictyostelium cyclic AMP GPCR to Rap1...
June 6, 2016: Developmental Cell
Taira Mayanagi, Hiroki Yasuda, Kenji Sobue
UNLABELLED: Dysregulation of synapse formation and plasticity is closely related to the pathophysiology of psychiatric and neurodevelopmental disorders. The prefrontal cortex (PFC) is particularly important for executive functions such as working memory, cognition, and emotional control, which are impaired in the disorders. PSD-Zip70 (Lzts1/FEZ1) is a postsynaptic density (PSD) protein predominantly expressed in the frontal cortex, olfactory bulb, striatum, and hippocampus. Here we found that PSD-Zip70 knock-out (PSD-Zip70KO) mice exhibit working memory and cognitive defects, and enhanced anxiety-like behaviors...
October 21, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Melissa L Vadnais, Haig K Aghajanian, Angel Lin, George L Gerton
Sperm motility encompasses a wide range of events involving epididymal maturation and activation of biochemical pathways, most notably cyclic AMP (cAMP)-protein kinase A (PKA) activation. Following the discovery of guanine-nucleotide exchange factors (RAPGEFs), also known as exchange proteins activated by cAMP, we investigated the separate roles of PKA and RAPGEFs in sperm motility. RT-PCR showed the presence of Rapgef3, Rapgef4, and Rapgef5, as well as several known RAPGEF partner mRNAs, in spermatogenic cells...
November 2013: Biology of Reproduction
Martijn Gloerich, Johannes L Bos
Signaling by the small G-protein Rap is under tight regulation by its GEFs and GAPs. These are multi-domain proteins that are themselves controlled by distinct upstream pathways, and thus couple different extra- and intracellular cues to Rap. The individual RapGEFs and RapGAPs are, in addition, targeted to specific cellular locations by numerous anchoring mechanisms and, consequently, may control different pools of Rap. Here, we review the various activating signals and targeting mechanisms of these proteins and discuss their contribution to the spatiotemporal regulation and biological functions of the Rap proteins...
October 2011: Trends in Cell Biology
Xiaoyun Dong, Christopher Korch, Judy L Meinkoth
Increases in Rap activity have been associated with tumor progression. Although activating mutations in Rap have not been described, downregulation of Rap1GAP is frequent in human tumors including thyroid carcinomas. In this study, we explored whether endogenous Rap1GAP expression could be restored to thyroid tumor cells. The effects of deacetylase inhibitors and a demethylating agent, individually and in combination, were examined in four differentiated and six anaplastic thyroid carcinoma (ATC) cell lines...
June 2011: Endocrine-related Cancer
Christina Spilker, Michael R Kreutz
Small Rap guanosine-tri-phosphate (GTP)ases are crucially involved in many cellular processes, including cell proliferation, differentiation, survival, adhesion and movement. In line, it has been shown that Rap signalling is involved in various aspects of neuronal differentiation, like the establishment of neuronal polarity or axonal growth cone movement. Rap GTPases can be activated by a wide variety of external stimuli, and this is mediated by specific guanine nucleotide exchange factors (RapGEFs). Inactivation of RapGTP can be achieved with the aid of specific GTPase-activating proteins (RapGAPs)...
July 2010: European Journal of Neuroscience
Zhiming Han, Namdori R Mtango, Zhisheng Zhong, Rita Vassena, Keith E Latham
Blastomere cytofragmentation in mammalian embryos poses a significant problem in applied and clinical embryology. Mouse two-cell-stage embryos display strain-dependent differences in the rate of cytofragmentation, with a high rate observed in C3H/HeJ embryos and a lower rate observed in C57BL/6 embryos. The maternally inherited genome exerts the strongest effect on the process, with lesser effects mediated by the paternally inherited genome and the ooplasm. The effect of the maternal genome is transcription dependent and independent of the mitochondrial strain of origin...
May 2010: American Journal of Physiology. Cell Physiology
Christel M Middeldorp, Jacqueline M Vink, John M Hettema, Eco J C de Geus, Kenneth S Kendler, Gonneke Willemsen, Michael C Neale, Dorret I Boomsma, Xiangning Chen
Deficiency in signal transduction might play a role in the development of anxiety and depression, as suggested by a study on the involvement of the PKA-independent Epac pathway. We investigated the association between Epac-1 gene variants, also known as RapGEF-3, and measures of anxiety and depression in a Dutch twin-family sample. Replication was sought in a USA sample consisting of unrelated individuals. Genotype and phenotype data were available for 910 Dutch and 684 USA individuals. Longitudinal self-report measures of neuroticism, anxiety and depression and genetic factor scores (GFS-NL), based on these measures, were analyzed in the Dutch sample...
January 5, 2010: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Willem-Jan Pannekoek, Matthijs R H Kooistra, Fried J T Zwartkruis, Johannes L Bos
Rap proteins are Ras-like small GTP-binding proteins that amongst others are involved in the control of cell-cell and cell-matrix adhesion. Several Rap guanine nucleotide exchange factors (RapGEFs) function to activate Rap. These multi-domain proteins, which include C3G, Epacs, PDZ-GEFs, RapGRPs and DOCK4, are regulated by various different stimuli and may function at different levels in junction formation. Downstream of Rap, a number of effector proteins have been implicated in junctional control, most notably the adaptor proteins AF6 and KRIT/CCM1...
April 2009: Biochimica et Biophysica Acta
M P Kelly, J M Stein, C G Vecsey, C Favilla, X Yang, S F Bizily, M F Esposito, G Wand, S J Kanes, T Abel
Schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippocampus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles...
April 2009: Molecular Psychiatry
Nadia Dubé, Matthijs R H Kooistra, Willem-Jan Pannekoek, Marjolein J Vliem, Viola Oorschot, Judith Klumperman, Holger Rehmann, Johannes L Bos
The small G-protein Rap1 is a critical regulator of cell-cell contacts and is activated by the remodeling of adherens junctions. Here we identify the Rap1 guanine nucleotide exchange factor PDZ-GEF2 as an upstream activator of Rap1 required for the maturation of adherens junctions in the lung carcinoma cells A549. Knockdown of PDZ-GEF2 results in the persistence of adhesion zippers at cell-cell contacts. Activation of Rap1A rescues junction maturation in absence of PDZ-GEF2, demonstrating that Rap1A is downstream of PDZ-GEF2 in this process...
September 2008: Cellular Signalling
W Pellis-van Berkel, M H G Verheijen, E Cuppen, M Asahina, J de Rooij, G Jansen, R H A Plasterk, J L Bos, F J T Zwartkruis
The Rap-pathway has been implicated in various cellular processes but its exact physiological function remains poorly defined. Here we show that the Caenorhabditis elegans homologue of the mammalian guanine nucleotide exchange factors PDZ-GEFs, PXF-1, specifically activates Rap1 and Rap2. Green fluorescent protein (GFP) reporter constructs demonstrate that sites of pxf-1 expression include the hypodermis and gut. Particularly striking is the oscillating expression of pxf-1 in the pharynx during the four larval molts...
January 2005: Molecular Biology of the Cell
J Clyde-Smith, G Silins, M Gartside, S Grimmond, M Etheridge, A Apolloni, N Hayward, J F Hancock
Ras proteins operate as molecular switches in signal transduction pathways downstream of tyrosine kinases and G-protein-coupled receptors. Ras is switched from the inactive GDP-bound state to the active GTP-bound state by guanine nucleotide exchange factors (GEFs). We report here the cloning and characterization of RasGRP2, a longer alternatively spliced form of the recently cloned RapGEF, CalDAG-GEFI. A unique feature of RasGRP2 is that it is targeted to the plasma membrane by a combination of N-terminal myristoylation and palmitoylation...
October 13, 2000: Journal of Biological Chemistry
J de Rooij, H Rehmann, M van Triest, R H Cool, A Wittinghofer, J L Bos
Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. A third member of the family, Repac (GFR), which lacks the cAMP dependent regulatory sequences, is a constitutive activator of both Rap1 and Rap2. In contrast to Epac1, Epac2 contains a second cAMP binding domain at the N terminus, as does the Epac homologue from Caenorhabditis elegans...
July 7, 2000: Journal of Biological Chemistry
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