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Liat Rahamim Ben-Navi, Tal Almog, Zhong Yao, Rony Seger, Zvi Naor
Mammalian spermatozoa undergo capacitation and acrosome reaction in order to fertilize the egg. The PKC-ERK1/2 pathway plays an important role in human spermatozoa motility, capacitation and the acrosome reaction. Here we demonstrate that ERK1/2 phosphorylates proAKAP4 on Thr265 in human spermatozoa in vitro and in vivo. Cyclic AMP (cAMP) had no effect on ERK1/2 activity in human spermatozoa, but stimulated the MAPK in mouse pituitary LβT2 gonadotrope cells. cAMP via PKA attenuates PKC-dependent ERK1/2 activation only in the presence of proAKAP4...
November 30, 2016: Scientific Reports
M Haidar, G Ramdani, E J Kennedy, G Langsley
The cAMP-dependent protein kinase PKA is a well-characterized member of the serine-threonine protein AGC kinase family and is the effector kinase of cAMP signaling. As such, PKA is involved in the control of a wide variety of cellular processes including metabolism, cell growth, gene expression and apoptosis. cAMP-dependent PKA signaling pathways play important roles during infection and virulence of various pathogens. Since fluxes in cAMP are involved in multiple intracellular functions, a variety of different pathological infectious processes can be affected by PKA signaling pathways...
November 11, 2016: Hormone and Metabolic Research, Hormon- und Stoffwechselforschung, Hormones et Métabolisme
Pascale Gerbaud, Fatima Ferreira, Guillaume Pidoux
In the human placenta, mononuclear cytotrophoblasts fuse to form multinucleated syncytia ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation. The syncytial formation is necessary for the maintenance of pregnancy and for fetal growth. The cAMP signaling pathway is the major route to trigger trophoblast fusion and its activation results in phosphorylation of specific intracellular target proteins and assembly of macromolecular protein complexes constituting the fusogenic machinery at the plasma membrane...
2016: Biologie Aujourd'hui
Jie Zhang, Chase M Carver, Frank S Choveau, Mark S Shapiro
The fidelity of neuronal signaling requires organization of signaling molecules into macromolecular complexes, whose components are in intimate proximity. The intrinsic diffraction limit of light makes visualization of individual signaling complexes using visible light extremely difficult. However, using super-resolution stochastic optical reconstruction microscopy (STORM), we observed intimate association of individual molecules within signaling complexes containing ion channels (M-type K(+), L-type Ca(2+), or TRPV1 channels) and G protein-coupled receptors coupled by the scaffolding protein A-kinase-anchoring protein (AKAP)79/150...
September 27, 2016: Neuron
Aleksandra R Dukic, David W McClymont, Kjetil Taskén
Connexin 43 (Cx43), the predominant gap junction (GJ) protein, directly interacts with the A-kinase-anchoring protein (AKAP) Ezrin in human cytotrophoblasts and a rat liver epithelial cells (IAR20). The Cx43-Ezrin-protein kinase (PKA) complex facilitates Cx43 phosphorylation by PKA, which triggers GJ opening in cytotrophoblasts and IAR20 cells and may be a general mechanism regulating GJ intercellular communication (GJIC). Considering the importance of Cx43 GJs in health and disease, they are considered potential pharmaceutical targets...
September 14, 2016: Journal of Biomolecular Screening
Kaare Bjerregaard-Andersen, Ellen Østensen, John D Scott, Kjetil Taskén, Jens Preben Morth
A-kinase anchoring proteins (AKAPs) are a family of proteins that provide spatiotemporal resolution of protein kinase A (PKA) phosphorylation. In the myocardium, PKA and AKAP18γ/δ are found in complex with sarcoendoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2) and phospholamban (PLB). This macromolecular complex provides a means by which anchored PKA can dynamically regulate cytoplasmic Ca(2+) release and re-uptake. For this reason, AKAP18γ/δ presents an interesting drug target with therapeutic potential in cardiovascular disease...
August 2016: Acta Crystallographica. Section F, Structural Biology Communications
Alessandro Dema, Micha Friedemann Schröter, Ekaterina Perets, Philipp Skroblin, Marie Christine Moutty, Veronika Anita Deàk, Walter Birchmeier, Enno Klussmann
The A-kinase anchoring protein (AKAP) GSK3β interaction protein (GSKIP) is a cytosolic scaffolding protein binding protein kinase A (PKA) and glycogen synthase kinase 3β (GSK3β). Here we show that both the AKAP function of GSKIP, i.e. its direct interaction with PKA, and its direct interaction with GSK3β are required for the regulation of β-catenin and thus Wnt signaling. A cytoplasmic destruction complex targets β-catenin for degradation and thus prevents Wnt signaling. Wnt signals cause β-catenin accumulation and translocation into the nucleus, where it induces Wnt target gene expression...
September 9, 2016: Journal of Biological Chemistry
Vanessa L Wehbi, Kjetil Taskén
The cyclic AMP/protein kinase A (cAMP/PKA) pathway is one of the most common and versatile signal pathways in eukaryotic cells. A-kinase anchoring proteins (AKAPs) target PKA to specific substrates and distinct subcellular compartments providing spatial and temporal specificity for mediation of biological effects channeled through the cAMP/PKA pathway. In the immune system, cAMP is a potent negative regulator of T cell receptor-mediated activation of effector T cells (Teff) acting through a proximal PKA/Csk/Lck pathway anchored via a scaffold consisting of the AKAP Ezrin holding PKA, the linker protein EBP50, and the anchoring protein phosphoprotein associated with glycosphingolipid-enriched microdomains holding Csk...
2016: Frontiers in Immunology
Verena A Bachmann, Johanna E Mayrhofer, Ronit Ilouz, Philipp Tschaikner, Philipp Raffeiner, Ruth Röck, Mathieu Courcelles, Federico Apelt, Tsan-Wen Lu, George S Baillie, Pierre Thibault, Pia Aanstad, Ulrich Stelzl, Susan S Taylor, Eduard Stefan
Scaffolding proteins organize the information flow from activated G protein-coupled receptors (GPCRs) to intracellular effector cascades both spatially and temporally. By this means, signaling scaffolds, such as A-kinase anchoring proteins (AKAPs), compartmentalize kinase activity and ensure substrate selectivity. Using a phosphoproteomics approach we identified a physical and functional connection between protein kinase A (PKA) and Gpr161 (an orphan GPCR) signaling. We show that Gpr161 functions as a selective high-affinity AKAP for type I PKA regulatory subunits (RI)...
July 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Carolina Morais Araujo, Milla Marques Hermidorff, Gabriela de Cassia Sousa Amancio, Denise da Silveira Lemos, Marcelo Estáquio Silva, Leonardo Vinícius Monteiro de Assis, Mauro César Isoldi
Aldosterone acts on its target tissue through a classical mechanism or through the rapid pathway through a putative membrane-bound receptor. Our goal here was to better understand the molecular and biochemical rapid mechanisms responsible for aldosterone-induced cardiomyocyte hypertrophy. We have evaluated the hypertrophic process through the levels of ANP, which was confirmed by the analysis of the superficial area of cardiomyocytes. Aldosterone increased the levels of ANP and the cellular area of the cardiomyocytes; spironolactone reduced the aldosterone-increased ANP level and cellular area of cardiomyocytes...
October 2016: Journal of Receptor and Signal Transduction Research
Chun-Chun Li, Kang Le, Jiro Kato, Joel Moss, Martha Vaughan
Multifunctional β-catenin, with critical roles in both cell-cell adhesion and Wnt-signaling pathways, was among HeLa cell proteins coimmunoprecipitated by antibodies against brefeldin A-inhibited guanine nucleotide-exchange factors 1 and 2 (BIG1 or BIG2) that activate ADP-ribosylation factors (Arfs) by accelerating the replacement of bound GDP with GTP. BIG proteins also contain A-kinase anchoring protein (AKAP) sequences that can act as scaffolds for multimolecular assemblies that facilitate and limit cAMP signaling temporally and spatially...
May 24, 2016: Proceedings of the National Academy of Sciences of the United States of America
Hong-Mei Li, Kang Guo, Xiao-Yun Yu, Zhuang Yu, Ping Xu
BACKGROUND: The A-kinase anchor proteins (AKAP) are a growing family of scaffolding proteins involved in the occurrence, proliferation, and metastasis of tumors by controlling intracellular signals. In this study, the expression and significance of AKAP4 were analyzed in patients with lung adenocarcinoma and adjacent non-cancerous tissues. METHODS: Using reverse transcriptase-polymerase chain reaction and Western blot, AKAP4 messenger ribonucleic acid (mRNA) and protein expression levels were measured in 108 cases of lung adenocarcinoma and adjacent non-cancerous tissues...
April 26, 2016: Thoracic Cancer
Cason R King, Michael J Cohen, Gregory J Fonseca, Brennan S Dirk, Jimmy D Dikeakos, Joe S Mymryk
The oncoproteins of the small DNA tumor viruses interact with a plethora of cellular regulators to commandeer control of the infected cell. During infection, adenovirus E1A deregulates cAMP signalling and repurposes it for activation of viral gene expression. We show that E1A structurally and functionally mimics a cellular A-kinase anchoring protein (AKAP). E1A interacts with and relocalizes protein kinase A (PKA) to the nucleus, likely to virus replication centres, via an interaction with the regulatory subunits of PKA...
May 2016: PLoS Pathogens
Gabriele Giacomo Schiattarella, Fabio Cattaneo, Gianluigi Pironti, Fabio Magliulo, Giuseppe Carotenuto, Marinella Pirozzi, Roman Polishchuk, Domenica Borzacchiello, Roberta Paolillo, Marco Oliveti, Nicola Boccella, Marisa Avvedimento, Maria Sepe, Assunta Lombardi, Rosa Anna Busiello, Bruno Trimarco, Giovanni Esposito, Antonio Feliciello, Cinzia Perrino
A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia...
2016: PloS One
Kossiwa Bandje, Bernina Naissant, Pascal Bigey, Murielle Lohezic, Marlène Vayssières, Magali Blaud, Laetitia Kermasson, José-Juan Lopez-Rubio, Gordon Langsley, Catherine Lavazec, Philippe Deloron, Anaïs Merckx
BACKGROUND: The asexual intra-erythrocytic multiplication of the malaria parasite Plasmodium falciparum is regulated by various molecular mechanisms. In eukaryotic cells, protein kinases are known to play key roles in cell cycle regulation and signaling pathways. The activity of cAMP-dependent protein kinase (PKA) depends on A-kinase anchoring proteins (AKAPs) through protein interactions. While several components of the cAMP dependent pathway-including the PKA catalytic and regulatory subunits-have been characterized in P...
2016: Malaria Journal
Frank Götz, Yvette Roske, Maike Svenja Schulz, Karolin Autenrieth, Daniela Bertinetti, Katja Faelber, Kerstin Zühlke, Annika Kreuchwig, Eileen J Kennedy, Gerd Krause, Oliver Daumke, Friedrich W Herberg, Udo Heinemann, Enno Klussmann
A-kinase anchoring proteins (AKAPs) interact with the dimerization/docking (D/D) domains of regulatory subunits of the ubiquitous protein kinase A (PKA). AKAPs tether PKA to defined cellular compartments establishing distinct pools to increase the specificity of PKA signalling. Here, we elucidated the structure of an extended PKA-binding domain of AKAP18β bound to the D/D domain of the regulatory RIIα subunits of PKA. We identified three hydrophilic anchor points in AKAP18β outside the core PKA-binding domain, which mediate contacts with the D/D domain...
July 1, 2016: Biochemical Journal
Zhi-Yan Hu, Yan-Ping Liu, Lin-Ying Xie, Xiao-Yan Wang, Fang Yang, Shi-You Chen, Zu-Guo Li
Our previous studies have shown that PRKA kinase anchor protein 9 (AKAP-9) is involved in colorectal cancer (CRC) cell proliferation and migration in vitro. However, whether or not AKAP-9 is important for CRC development or metastasis in vivo remains unknown. In the present study, we found that AKAP-9 expression was significantly higher in human colorectal cancer tissues than the paired normal tissues. In fact, AKAP-9 level correlated with the CRC infiltrating depth and metastasis. Moreover, the higher AKAP-9 expression was associated with the lower survival rate in patients...
June 2016: Biochimica et Biophysica Acta
Pepijn P Burgers, Jessica Bruystens, Rebecca J Burnley, Viacheslav O Nikolaev, Malik Keshwani, Jian Wu, Bert J C Janssen, Susan S Taylor, Albert J R Heck, Arjen Scholten
UNLABELLED: The A-kinase anchoring protein (AKAP) smAKAP has three extraordinary features; it is very small, it is anchored directly to membranes by acyl motifs, and it interacts almost exclusively with the type I regulatory subunits (RI) of cAMP-dependent kinase (PKA). Here, we determined the crystal structure of smAKAP's A-kinase binding domain (smAKAP-AKB) in complex with the dimerization/docking (D/D) domain of RIα which reveals an extended hydrophobic interface with unique interaction pockets that drive smAKAP's high specificity for RI subunits...
June 2016: FEBS Journal
Jennifer L Sanderson, Jessica A Gorski, Mark L Dell'Acqua
Information processing in the brain requires multiple forms of synaptic plasticity that converge on regulation of NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR), including long-term potentiation (LTP) and long-term depression (LTD) and homeostatic scaling. In some cases, LTP and homeostatic plasticity regulate synaptic AMPAR subunit composition to increase the contribution of Ca(2+)-permeable receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits. Here, we show that PKA anchored to the scaffold protein AKAP150 regulates GluA1 phosphorylation and plays a novel role controlling CP-AMPAR synaptic incorporation during NMDAR-dependent LTD...
March 2, 2016: Neuron
Sabrina Villalpando, Chantal Cazevieille, Anne Fernandez, Ned J Lamb, El-Habib Hani
Specificity of the cAMP-dependent protein kinase (PKA) pathway relies on an extremely sophisticated compartmentalization mechanism of the kinase within a given cell, based on high-affinity binding of PKA tetramer pools to different A-Kinase Anchoring Proteins (AKAPs). We and others have previously shown that AKAPs-dependent PKA subcellular targeting is a requisite for optimal cAMP-dependent potentiation of insulin exocytosis. We thus hypothesized that a PKA pool may directly anchor to the secretory compartment to potentiate insulin exocytosis...
June 2016: Biochimie
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