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      Akt isoforms in vascular disease

      review-article
      a , * , b , a
      Vascular Pharmacology
      Elsevier Science
      Akt, oncogene identified in the Akt8 retrovirus, ApoE, apolipoprotein E, FOXO, forkhead class O transcription factor, HDL, high-density lipoprotein, OHT, 4-hydroxytamoxifen, IGF, insulin-like growth factor, LDL, low-density lipoprotein, SM22α, smooth muscle protein 22α (tagln), TUNEL, terminal deoxynucleotidyl transferase UTP end labelling, VSMC, vascular smooth muscle cell, MMP, matrix metalloproteinase, TIMP, tissue inhibitors of metalloproteinase, ADAM, a disintegrin and metalloproteinase, ECM, extracellular matrix, GSK, glycogen synthase kinase, AAA, abdominal aortic aneurysm, TAA, thoracic aortic aneurysm, eNOS, endothelial nitric oxide synthase, mTOR, mammalian target of rapamycin, Vascular diseases, Atherosclerosis, Akt, Aneurysm

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          Abstract

          The mammalian serine/threonine Akt kinases comprise three closely related isoforms: Akt1, Akt2 and Akt3. Akt activation has been implicated in both normal and disease processes, including in development and metabolism, as well as cancer and cardiovascular disease. Although Akt signalling has been identified as a promising therapeutic target in cancer, its role in cardiovascular disease is less clear. Importantly, accumulating evidence suggests that the three Akt isoforms exhibit distinct tissue expression profiles, localise to different subcellular compartments, and have unique modes of activation. Consistent with in vitro findings, genetic studies in mice show distinct effects of individual Akt isoforms on the pathophysiology of cardiovascular disease. This review summarises recent studies of individual Akt isoforms in atherosclerosis, vascular remodelling and aneurysm formation, to provide a comprehensive overview of Akt function in vascular disease.

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          Most cited references65

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          Cellular motility driven by assembly and disassembly of actin filaments.

          Motile cells extend a leading edge by assembling a branched network of actin filaments that produces physical force as the polymers grow beneath the plasma membrane. A core set of proteins including actin, Arp2/3 complex, profilin, capping protein, and ADF/cofilin can reconstitute the process in vitro, and mathematical models of the constituent reactions predict the rate of motion. Signaling pathways converging on WASp/Scar proteins regulate the activity of Arp2/3 complex, which mediates the initiation of new filaments as branches on preexisting filaments. After a brief spurt of growth, capping protein terminates the elongation of the filaments. After filaments have aged by hydrolysis of their bound ATP and dissociation of the gamma phosphate, ADF/cofilin proteins promote debranching and depolymerization. Profilin catalyzes the exchange of ADP for ATP, refilling the pool of ATP-actin monomers bound to profilin, ready for elongation.
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            Cellular survival: a play in three Akts.

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              Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L)

              Extracellular survival factors alter a cell's susceptibility to apoptosis, often through posttranslational mechanisms. However, no consistent relationship has been established between such survival signals and the BCL-2 family, where the balance of death agonists versus antagonists determines susceptibility. One distant member, BAD, heterodimerizes with BCL-X(L) or BCL-2, neutralizing their protective effect and promoting cell death. In the presence of survival factor IL-3, cells phosphorylated BAD on two serine residues embedded in 14-3-3 consensus binding sites. Only the nonphosphorylated BAD heterodimerized with BCL-X(L) at membrane sites to promote cell death. Phosphorylated BAD was sequestered in the cytosol bound to 14-3-3. Substitution of serine phosphorylation sites further enhanced BAD's death-promoting activity. The rapid phosphorylation of BAD following IL-3 connects a proximal survival signal with the BCL-2 family, modulating this checkpoint for apoptosis.
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                Author and article information

                Contributors
                Journal
                Vascul Pharmacol
                Vascul. Pharmacol
                Vascular Pharmacology
                Elsevier Science
                1537-1891
                1879-3649
                1 August 2015
                August 2015
                : 71
                : 57-64
                Affiliations
                [a ]Division of Cardiovascular Medicine, University of Cambridge, Box 110, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
                [b ]Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
                Author notes
                [* ]Corresponding author. Tel.: + 44 1223 331504; fax: + 44 1223 331505. hy258@ 123456cam.ac.uk
                Article
                S1537-1891(15)00039-7
                10.1016/j.vph.2015.03.003
                4728195
                25929188
                b57e2456-32e8-4cfc-80c6-d0ae51dd8409
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 9 January 2015
                : 31 March 2015
                Categories
                Review

                Pharmacology & Pharmaceutical medicine
                akt, oncogene identified in the akt8 retrovirus,apoe, apolipoprotein e,foxo, forkhead class o transcription factor,hdl, high-density lipoprotein,oht, 4-hydroxytamoxifen,igf, insulin-like growth factor,ldl, low-density lipoprotein,sm22α, smooth muscle protein 22α (tagln),tunel, terminal deoxynucleotidyl transferase utp end labelling,vsmc, vascular smooth muscle cell,mmp, matrix metalloproteinase,timp, tissue inhibitors of metalloproteinase,adam, a disintegrin and metalloproteinase,ecm, extracellular matrix,gsk, glycogen synthase kinase,aaa, abdominal aortic aneurysm,taa, thoracic aortic aneurysm,enos, endothelial nitric oxide synthase,mtor, mammalian target of rapamycin,vascular diseases,atherosclerosis,akt,aneurysm

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