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Micah B Schott, Faith Gonowolo, Benjamin Maliske, Bryon Grove
Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can traffic to different subcellular compartments upon stimulation. Gravin (AKAP12), a multivalent scaffold, anchors PKA and other enzymes to the plasma membrane under basal conditions, but upon [Ca(2+)]i elevation, is rapidly redistributed to the cytosol. Because gravin redistribution also impacts PKA localization, we postulate that gravin acts as a calcium "switch" that modulates PKA-substrate interactions at the plasma membrane, thus facilitating a novel crosstalk mechanism between Ca(2+) and PKA-dependent pathways...
April 2016: Cellular Signalling
Wei Xia, Jing Ni, Juhua Zhuang, Leixing Qian, Peng Wang, Jiening Wang
AKAP12/Gravin (A kinase anchor protein 12) belongs to the group of A-kinase scaffold proteins and functions as a tumor suppressor in some human primary cancers. While AKAP12 is found consistently downregulated in hepatocellular carcinoma (HCC), its involvement in hepatocarcinogenesis has not been fully elucidated. We identified targeting sites for miR-103 in the 3'-untranslated region (3'-UTR) of AKAP12 by bioinformatic analysis and confirm their function by a luciferase reporter gene assay. We reveal miR-103 expression to be inversely correlated with AKAP12 in HCC tissue samples and show that overexpressed miR-103 promotes cell proliferation and inhibits apoptosis by downregulating AKAP12 expression in HCC cell lines...
February 2016: International Journal of Biochemistry & Cell Biology
Heidi Hehnly, David Canton, Paula Bucko, Lorene K Langeberg, Leah Ogier, Irwin Gelman, L Fernando Santana, Linda Wordeman, John D Scott
Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase...
September 25, 2015: ELife
S Weninger, K Van Craenenbroeck, R T Cameron, F Vandeput, M A Movsesian, G S Baillie, R A Lefebvre
Phosphodiesterase (PDE) 3 and PDE4, which degrade cyclic adenosine monophosphate (cAMP), are important regulators of 5-hydroxytryptamine (5-HT) 4 receptor signaling in cardiac tissue. Therefore, we investigated whether they interact with the 5-HT4(b) receptor, and whether A-kinase anchoring proteins (AKAPs), scaffolding proteins that bind to the regulatory subunit of protein kinase A (PKA) and contribute to the spacial-temporal control of cAMP signaling, are involved in the regulation of 5-HT4(b) receptor signaling...
November 2014: Cellular Signalling
Hyun-Kyung Ko, Shin Akakura, Jennifer Peresie, David W Goodrich, Barbara A Foster, Irwin H Gelman
The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia...
February 1, 2014: Cancer Research
M Yildirim, D Suren, M Yildiz, A Sezgin Alikanoglu, R Eryilmaz, S Goktas, N Bulbuller, C Sezer
PURPOSE: : Colorectal cancer (CRC) is a common and potentially lethal disease. A number of genetic aberrations is known to take place in colorectal carcinogenesis, which leads to progressive alteration of normal mechanisms controlling cell growth. A-kinase-anchoring protein 12 (AKAP12) plays a role in cell proliferation, angiogenesis and cytoskeletal remodeling. The purpose of this study was to demonstrate the role of the AKAP12 gene expression in CRC patients and to determine its relationship (if any) with prognosis...
July 2013: Journal of B.U.ON.: Official Journal of the Balkan Union of Oncology
Ashley N Guillory, Xing Yin, Cori S Wijaya, Andrea C Diaz Diaz, Abeer Rababa'h, Sonal Singh, Fatin Atrooz, Sakthivel Sadayappan, Bradley K McConnell
Gravin, an A-kinase anchoring protein, targets protein kinase A (PKA), protein kinase C (PKC), calcineurin and other signaling molecules to the beta2-adrenergic receptor (β2-AR). Gravin mediates desensitization/resensitization of the receptor by facilitating its phosphorylation by PKA and PKC. The role of gravin in β-AR mediated regulation of cardiac function is unclear. The purpose of this study was to determine the effect of acute β-AR stimulation on cardiac contractility in mice lacking functional gravin...
2013: PloS One
Thomas Weissmüller, Louise E Glover, Blair Fennimore, Valerie F Curtis, Christopher F MacManus, Stefan F Ehrentraut, Eric L Campbell, Melanie Scully, Bryon D Grove, Sean P Colgan
Hypoxia has been widely implicated in many pathological conditions, including those associated with inflammation and tumorigenesis. A number of recent studies have implicated hypoxia in the control of vasculogenesis and permeability, the basis for which is not fully understood. Here we examine the transcriptional regulation of angiogenesis and permeability by hypoxia in endothelial cells. Guided by a global profiling approach in cultured endothelial cells, these studies revealed the selective induction of human gravin (protein kinase A anchoring protein 12) by hypoxia...
January 2014: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Micah B Schott, Bryon Grove
A-Kinase Anchoring Proteins (AKAPs) direct the flow of cellular information by positioning multiprotein signaling complexes into proximity with effector proteins. However, certain AKAPs are not stationary but can undergo spatiotemporal redistribution in response to stimuli. Gravin, a 300kD AKAP that intersects with a diverse signaling array, is localized to the plasma membrane but has been shown to translocate to the cytosol following the elevation of intracellular calcium ([Ca(2+)]i). Despite the potential for gravin redistribution to impact multiple signaling pathways, the dynamics of this event remain poorly understood...
November 2013: Cellular Signalling
Mohamed R Mostafa, Raida S Yahia, Hanaa M Abd El Messih, Eman El-Sisy, Doaa M El Ghannam
Acute leukemias are caused by genetic and epigenetic mechanisms involving tumor suppressor genes and oncogenes. Aberrant DNA methylation patterns are the most frequent molecular alterations detected in acute myeloid leukemia (AML). Gravin is down-regulated in several solid tumors and is implicated in tumorigenesis. To explore its role in the molecular pathogenesis and its possible prognostic importance in AML, we have evaluated the expression levels of the gravin gene in 83 acute myeloid leukemia patients as compared with controls using quantitative real-time polymerase chain reaction (qRT-PCR)...
June 2013: Medical Oncology
Robbert Havekes, David A Canton, Alan J Park, Ted Huang, Ting Nie, Jonathan P Day, Leonardo A Guercio, Quinn Grimes, Vincent Luczak, Irwin H Gelman, George S Baillie, John D Scott, Ted Abel
A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage...
December 12, 2012: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
David A Canton, C Dirk Keene, Katie Swinney, Lorene K Langeberg, Vivian Nguyen, Laurence Pelletier, Tony Pawson, Linda Wordeman, Nephi Stella, John D Scott
The mitogenic and second-messenger signals that promote cell proliferation often proceed through multienzyme complexes. The kinase-anchoring protein Gravin integrates cAMP and calcium/phospholipid signals at the plasma membrane by sequestering protein kinases A and C with G protein-coupled receptors. In this report we define a role for Gravin as a temporal organizer of phosphorylation-dependent protein-protein interactions during mitosis. Mass spectrometry, molecular, and cellular approaches show that CDK1/Cyclin B1 phosphorylates Gravin on threonine 766 to prime the recruitment of the polo-like kinase Plk1 at defined phases of mitosis...
November 30, 2012: Molecular Cell
Shin Akakura, Irwin H Gelman
Cellular dynamics are controlled by key signaling molecules such as cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). AKAP12/SSeCKS/Gravin (AKAP12) is a scaffold protein for PKA and PKC which controls actin-cytoskeleton reorganization in a spatiotemporal manner. AKAP12 also acts as a tumor suppressor which regulates cell-cycle progression and inhibits Src-mediated oncogenic signaling and cytoskeletal pathways. Reexpression of AKAP12 causes cell flattening, reorganization of the actin cytoskeleton, and the production of normalized focal adhesion structures...
2012: Journal of Signal Transduction
B Su, L Gao, F Meng, L-W Guo, J Rothschild, I H Gelman
Metastatic cell migration and invasion are regulated by altered adhesion-mediated signaling to the actin-based cytoskeleton via activated Src-FAK complexes. Src-suppressed C-kinase substrate (SSeCKS, the rodent orthologue of human Gravin/AKAP12), whose expression is downregulated by oncogenic Src and in many human cancers, antagonizes oncogenic Src pathways including those driving neovascularization at metastatic sites, metastatic cell motility and invasiveness. This is likely manifested through its function as a scaffolder of F-actin and signaling proteins such as cyclins, calmodulin, protein kinase C and A...
April 18, 2013: Oncogene
Irwin H Gelman
Scaffolding proteins such as SSeCKS/Gravin/AKAP12 ("AKAP12") are thought to control oncogenic signaling pathways by regulating key mediators in a spatiotemporal manner. The downregulation of AKAP12 in many human cancers, often associated with promoter hypermethylation, or the loss of its locus at 6q24-25.2, correlates with progression to malignancy and metastasis. The forced re-expression of AKAP12 in cancer cell lines suppresses in vitro parameters of oncogenic growth, invasiveness, and cell motility through its ability to scaffold protein kinase C (PKC), F-actin, cyclins, Src, and phosphoinositides, and possibly through additional scaffolding domains for PKA, calmodulin, β1,4-galactosyltransferase-polypeptide-1, β2-adrenergic receptors, and cAMP-specific 3',5'-cyclic phosphodiesterase 4D...
December 2012: Cancer Metastasis Reviews
Sarah J Horvat, Deepak A Deshpande, Huandong Yan, Reynold A Panettieri, Juan Codina, Thomas D DuBose, Wenkuan Xin, Thomas C Rich, Raymond B Penn
A-kinase anchoring proteins (AKAPs) have emerged as important regulatory molecules that can compartmentalize cAMP signaling transduced by β2-adrenergic receptors (β(2)ARs); such compartmentalization ensures speed and fidelity of cAMP signaling and effects on cell function. This study aimed to assess the role of AKAPs in regulating global and compartmentalized β(2)AR signaling in human airway smooth muscle (ASM). Transcriptome and proteomic analyses were used to characterize AKAP expression in ASM. Stable expression or injection of peptides AKAP-IS or Ht31 was used to disrupt AKAP-PKA interactions, and global and compartmentalized cAMP accumulation stimulated by β-agonist was assessed by radioimmunoassay and membrane-delineated flow through cyclic nucleotide-gated channels, respectively...
September 2012: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Weiwei Liu, Ming Guan, Tingting Hu, Xiaoye Gu, Yuan Lu
BACKGROUND: AKAP12/Gravin (A kinase anchor protein 12) is one of the A-kinase scaffold proteins and a potential tumor suppressor gene in human primary cancers. Our recent study demonstrated the highly recurrent loss of AKAP12 in colorectal cancer and AKAP12 reexpression inhibited proliferation and anchorage-independent growth in colorectal cancer cells, implicating AKAP12 in colorectal cancer pathogenesis. METHODS: To evaluate the effect of this gene on the progression and metastasis of colorectal cancer, we examined the impact of overexpressing AKAP12 in the AKAP12-negative human colorectal cancer cell line LoVo, the single clone (LoVo-AKAP12) compared to mock-transfected cells (LoVo-CON)...
2011: PloS One
Li-Wu Guo, Lingqiu Gao, Julian Rothschild, Bing Su, Irwin H Gelman
The product of the SSeCKS/GRAVIN/AKAP12 gene ("SSeCKS") is a major protein kinase (PK) C substrate that exhibits tumor- and metastasis-suppressing activity likely through its ability to scaffold multiple signaling mediators such as PKC, PKA, cyclins, calmodulin, and Src. Although SSeCKS and PKCα bind phosphatidylserine, we demonstrate that phosphatidylserine-independent binding of PKC by SSeCKS is facilitated by two homologous SSeCKS motifs, EG(I/V)(T/S)XWXSFK(K/R)(M/L)VTP(K/R)K(K/R)X(K/R)XXXEXXXE(E/D) (amino acids 592-620 and 741-769)...
November 4, 2011: Journal of Biological Chemistry
Irwin H Gelman
Emerging data suggest that SSeCKS/Gravin/AKAP12 ("AKAP12"), originally identified as an autoantigen in cases of myasthenia gravis, controls multiple biological processes through its ability to scaffold key signaling proteins such as protein kinase (PK) C and A, calmodulin, cyclins, phosphoinositides, "long" β-1,4 galactosyltransferase (GalTase) isoform, Src, as well as the actin cytoskeleton in a spatiotemporal manner. Specialized functions attributed to AKAP12 include the suppression of cancer malignancy, especially aspects of metastatic progression, regulation of blood-brain and blood-retina barrier formation, and resensitization of β2-adrenergic pain receptors...
November 2010: Genes & Cancer
Shujuan Gao, Hsien-Yu Wang, Craig C Malbon
BACKGROUND: A-kinase-anchoring proteins, AKAPs, constitute a family of scaffolds that play an essential role in catalyzing the spatial-temporal, dynamic interactions of protein kinase A, protein kinase C, tyrosine kinases, G-protein-coupled receptors and ion channels. We studied AKAP5 (AKAP79; MW ~47 kDa) and AKAP12 (gravin, SSECKS; MW ~191 kDa) to probe if these AKAP scaffolds oligomerize. RESULTS: In gel analysis and sodium-dodecyl sulfate denaturation, AKAP12 behaved with a MW of a homo-dimer...
2011: Journal of Molecular Signaling
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