The Identification of ATP-citrate Lyase as a Protein Kinase B (Akt) Substrate in Primary Adipocytes

Berwick, Daniel C.; Hers, Ingeborg; Heesom, Kate J; Moule, S K; Tavaré, Jeremy M.

doi:10.1074/jbc.m204681200

Cited by 324 publications

(290 citation statements)

References 45 publications

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“…Three lines of evidence strongly suggest that the 54 phosphorylated sites we discovered are indeed induced in response to b2-AR/cAMP signaling. First, 9 of the 54 phosphosites we identified are previously known cAMP-stimulated sites (Berwick et al, 2002;Gunaratne et al, 2010;Lundby et al, 2013;Yip et al, 2014). Second, we found enrichment of the amino acid motif R/K-X-pS (p , 1.0 Â 10 2 8 by Fisher's exact test; Supplemental Fig.…”

Section: Pronounced Differences In Upstream Cellularmentioning

confidence: 84%

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

Tsvetanova

Trester-Zedlitz²,

Newton³

et al. 2016

Mol Pharmacol

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The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse b-adrenoceptor agonists, isoproterenol and salmeterol. We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis. We further demonstrate that the endosomal b2-adrenergic receptor signal confers uniformity on the downstream response because it is highly sensitive and saturable. Based on these findings, we propose that GPCR signaling from endosomes functions as a biologic noise filter to enhance reliability of cognate ligand detection.

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Section: Pronounced Differences In Upstream Cellularmentioning

confidence: 84%

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

Tsvetanova

Trester-Zedlitz²,

Newton³

et al. 2016

Mol Pharmacol

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“…Other substrates identified through peptide and protein library screening defined Akt substrate motifs as RXRXRXXS where the R at position Ϫ7 (i.e. 7 amino acids upstream of S) is important for Akt phosphorylation (31), and R at Ϫ5 is dispensable (32). Akt also can phosphorylate actin on sequences XXXXRXXS (33), which is divergent from its consensus sequences.…”

Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Gao

Tang

Guo

et al. 2008

Journal of Biological Chemistry

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Increased expression of adenylyl cyclase VI has beneficial effects on the heart, but strategies that increase cAMP production in cardiac myocytes usually are harmful. Might adenylyl cyclase VI have beneficial effects unrelated to increased ␤-adrenergic receptor-mediated signaling? We previously reported that adenylyl cyclase VI reduces cardiac phospholamban expression. Our focus in the current studies is how adenylyl cyclase VI influences phospholamban phosphorylation. In cultured cardiac myocytes, increased expression of adenylyl cyclase VI activates Akt by phosphorylation at serine 473 and threonine 308 and is associated with increased nuclear phospho-Akt. Activated Akt phosphorylates phospholamban, a process that does not require ␤-adrenergic receptor stimulation or protein kinase A activation. These previously unrecognized signaling events would be predicted to promote calcium handling and increase contractile function of the intact heart independently of ␤-adrenergic receptor activation. We speculate that phospholamban phosphorylation, through activation of Akt, may be an important mechanism by which adenylyl cyclase VI increases the function of the failing heart. Adenylyl cyclase (AC) 4 catalyzes ATP to generate cAMP, a second messenger that is required for many intracellular events. AC is the effector molecule in the ␤-adrenergic receptor (␤AR)-Gs-AC signaling pathway and for many other G-protein-coupled receptors in cardiac myocytes and other cells (1-2). Cardiac myocytes express predominantly AC type V and AC type VI (AC VI ) (3). Cardiac-directed expression of AC VI in murine cardiomyopathy increases cardiac function, attenuates myocardial hypertrophy, and increases survival (4, 5). However, when cardiac-directed ␤AR expression is used in this same model, life is shortened (6, 7). Clearly there are marked differences in effects that are evoked by these two elements in the ␤AR-Gs-AC signaling pathway, even though both strategies increase cAMP.The objective of the current study was to determine whether increased AC VI expression has effects not directly linked with ␤AR stimulation and protein kinase A (PKA) activation, thereby providing a mechanistic explanation for the unanticipated favorable effects of increased cardiac AC VI expression in heart failure. We previously reported that AC VI reduces cardiac phospholamban (PLB) expression through increased expression of activating transcription factor-3, which suppresses PLB promoter activity (8). We now focus on how AC VI influences PLB phosphorylation. We test the hypothesis that AC VI increases PLB phosphorylation independently of ␤AR stimulation and PKA activation. This would result in increased cardiac function but would circumvent deleterious effects of sustained PKA activation (9).

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“…ACL is a ho mote trameric en zyme lo cated in the cy to plasm. It is ATP de pen dent and ac ti vated by AKT [20]. Sev eral stud ies have sug gested that in hi bi tion of ACL [17,21] and fatty acid syn the sis [22,23] can limit tu mori ge n e sis.…”

Section: Metabolic Contribution To Cell Proliferationmentioning

confidence: 99%

Cancer metabolism in space and time: Beyond the Warburg effect

Danhier

Bański

Payen

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

162

134

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Available online xxx Keywords:Can cer Me tab o lism Mi to chon dria Het ero gene ity Metas ta sis A B S T R A C T Al tered me tab o lism in can cer cells is piv otal for tu mor growth, most no tably by pro vid ing en ergy, re duc ing equiv a lents and build ing blocks while sev eral metabo lites ex ert a sig nal ing func tion pro mot ing tu mor growth and pro gres sion. A can cer tis sue can not be sim ply re duced to a bulk of pro lif er at ing cells. Tu mors are in deed com plex and dy namic struc tures where sin gle cells can het ero ge neously per form var i ous bi o log i cal ac tiv i ties with dif fer ent meta bolic re quire ments. Be cause tu mors are com posed of dif fer ent types of cells with meta bolic ac tiv i ties af fected by dif fer ent spa tial and tem po ral con texts, it is im por tant to ad dress me tab o lism tak ing into ac count cel lu lar and bi o log i cal het ero gene ity. In this re view, we de scribe this het ero gene ity also in meta bolic fluxes, thus show ing the rel a tive con tri bu tion of dif fer ent meta bolic ac tiv i ties to tu mor pro gres sion ac cord ing to the cel lu lar con text. This ar ti cle is part of a Spe cial Is sue en ti tled Res pi ra tory com plex I, edited by Giuseppe Gas parre, Ro drigue Rossig nol and Pierre Son veaux. Abbreviations: ACL, ATP cit rate lyase; AMPK, adeno sine monophos phate ki nase; ARG1, L argi nine me tab o liz ing en zyme arginase 1; BCAA, branched chain amino acid; Bcl2, B cell lym phoma 2; CAF, can cer as so ci ated fi brob last; CIC, can cer ini ti at ing cell; COX2, cy tochrome ox i dase; CSC, can cer stem cell; CREB, cyclic adeno sine monophos phate re sponse el e ment bind ing pro tein; DEC1, dif fer en tially ex pressed in chon dro cytes 1; EMT, ep ithe lial to mes enchy mal tran si tion; FAK, fo cal ad he sion ki nase; FAS, fatty acid syn thase; FBP, fruc tose 1,6 bis pho s phate; FDG PET, [ F] flu o rodeoxyglu cose positron emis sion to mog ra phy; GAPDH, glyc er alde hyde 3 phos phate de hy dro ge nase; HIF 1, hy poxia ac ti vated fac tor 1; HK2, hex ok i nase 2; HMGB1, high mo bil ity group box 1; HU VEC, hu man um bil i cal vein en dothe lial cell; IFN γ, in ter feron gamma; LDH, lac tate de hy dro ge nase; MEF, murine em bry onic fi brob last; MET, mes enchy mal to ep ithe lial tran si tion; MRI, mag netic res o nance imag ing; mTORC1, mam malian tar get of ra pamycin com plex 1; NSCLC, non small cell lung can cer; OX PHOS, ox ida tive phos pho ry la tion; PDAC, pan cre atic duc tal ade no car ci noma; PHD, pro lyl hy drox y lase; pHe, ex tra cel lu lar pH; pHi, in tra cel lu lar pH; PK, pyru vate ki nase; PPP, pen tose phos phate path way; REDD1, reg u lated in de vel op ment and DNA dam age re sponse 1; RhoA, Ras ho molog gene fam ily, mem ber A; ROS, re ac tive oxy gen species; SASP, senes cence as so ci ated se cre tory phe no type; SCO2, syn the sis of cy tochrome ox i dase 2; SGK 1, serum and glu co cor ti coid reg u lated ki nase 1 Sirt1, sir tuin 1; TAM, tu mor as so ci ated macrophage; TIGAR, TP53 in duced gly col y ...

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The Identification of ATP-citrate Lyase as a Protein Kinase B (Akt) Substrate in Primary Adipocytes

Cited by 324 publications

References 45 publications

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

G Protein–Coupled Receptor Endocytosis Confers Uniformity in Responses to Chemically Distinct Ligands

Adenylyl Cyclase Type VI Increases Akt Activity and Phospholamban Phosphorylation in Cardiac Myocytes

Cancer metabolism in space and time: Beyond the Warburg effect

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