PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration

Fleming, Yvonne; Frame, Margaret C.; Houslay, Miles D.

doi:10.1242/jcs.01096

Cited by 43 publications

(50 citation statements)

References 61 publications

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“…Interestingly, altered motility was paralleled by a reduced capacity for cells to reorganize their actin cytoskeleton, to promote the formation of actin spike, and to change their shape following contact with ECM (46). This result is in line with previous observations showing that hERG expression contributes to morphology, actin cytoskeleton dynamics, and finally cell migration behavior (11).…”

Section: Discussionsupporting

confidence: 89%

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

et al. 2016

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The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K þ channel human ether-a-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/b1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/ AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating crosstalk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition. Cancer Res; 76(3); 607-18. Ó2015 AACR.

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Section: Discussionsupporting

confidence: 89%

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

et al. 2016

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“…In this context, studies using bovine (bAEC) or human (HUVEC) cells have indicated that increasing VEC cAMP levels may represent a novel therapeutic approach to achieving this goal (Favot et al, 2003;Fleming et al, 2004). Although these earlier studies showed that this approach could work in model systems, they did not assess its potential in microvascular beds, vascular structures that are more likely to be involved in supplying VECs for angiogenesis in vivo in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Most effects of cAMP or cGMP are thought to be related to activation of protein kinase A or protein kinase G, respectively, and phosphorylation of multiple selective cellular substrates (D'Angelo et al, 1997;Fleming et al, 2004). Cellular cAMP and cGMP levels are dynamically regulated by both the rate of their synthesis by cyclases and their hydrolysis by cyclic nucleotide phosphodiesterases (PDEs).…”

mentioning

confidence: 99%

Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Netherton

Maurice²

2004

Mol Pharmacol

114

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Angiogenesis is necessary during embryonic development and wound healing but can be detrimental in pathologies, including cancer. Because initiation of angiogenesis involves migration and proliferation of vascular endothelial cells (VECs) and cAMPelevating agents inhibit these events, such agents may represent a novel therapeutic avenue to controlling angiogenesis. Intracellular cAMP levels are regulated by their synthesis by adenylyl cyclases and hydrolysis by cyclic nucleotide phosphodiesterases (PDEs). In this report, we show that human VECs express variants of PDE2, PDE3, PDE4, and PDE5 families and demonstrate that the levels of these enzymes differ in VECs derived from aorta, umbilical vein, and microvascular structures. Selective inhibition of PDE2 did not increase cAMP in any VECs, whether in the absence or presence of forskolin, but it did inhibit migration of all VECs studied. Inhibition of PDE4 activity decreased migration, and in conjunction with forskolin, increased cAMP in all VECs studied. PDE3 inhibition potentiated forskolin-induced increases in cAMP and inhibited migration in VECs derived from aorta and umbilical vein but not in microvascular VECs. In experiments with combinations of PDE2, PDE3, and PDE4 inhibitors, a complex interaction between the abilities of these agents to limit human VEC migration was observed. Overall, our data are consistent with the hypothesis that PDE subtype inhibition allows different effects in distinct VEC populations and indicate that these agents may represent novel therapeutic agents to limit angiogenesis in complex human diseases.

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“…Plasmids encoding FLAG-DISC1, mycHIS-fl-DISC1, mycHIS-(⌬1-187)-DISC1, PKA inhibitory peptide PKI, and PDE4 constructs PDE4A5, PDE4B1, PDEB2, PDEB3, PDE4C2, PDE4D3, PDE4D5, PDE4D3S54A, PDE4D3S54E, PDE4D3S13AS54A, and PDE4D-CAT have been described previously (Huston et al, 1996(Huston et al, , 1997Bolger et al, 1997;Owens et al, 1997;Hoffmann et al, 1998;Beard et al, 2000;Brandon et al, 2004;Fleming et al, 2004;Millar et al, 2005). DISC1 regions comprising residues 220 -283 and 359 -854 were subcloned into pEBG-2T vector to generate GST fusion proteins for expression in mammalian cells.…”

Section: Methodsmentioning

confidence: 99%

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

Murdoch¹,

Mackie²,

Collins³

et al. 2007

J. Neurosci.

146

164

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Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology.

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PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration

Cited by 43 publications

References 61 publications

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

Vascular Endothelial Cell Cyclic Nucleotide Phosphodiesterases and Regulated Cell Migration: Implications in Angiogenesis

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

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