Abstract
The BH3-only pro-apoptotic proteins are upstream sensors of cellular damage that selectively respond to specific, proximal death and survival signals. Genetic models and biochemical studies indicate that these molecules are latent killers until activated through transcriptional or post-translational mechanisms in a tissue-restricted and signal-specific manner. The large number of BH3-only proteins, their unique subcellular localization, protein-interaction network and diverse modes of activation suggest specialization of their damage-sensing function, ensuring that the core apoptotic machinery is poised to receive input from a wide range of cellular stress signals. The apoptotic response initiated by the activation of BH3-only proteins ultimately culminates in allosteric activation of pro-apoptotic BAX and BAK, the gateway proteins to the mitochondrial pathway of apoptosis. From activation of BH3-only proteins to oligomerization of BAX and BAK and mitochondrial outer membrane permeabilization, an intricate network of interactions between the pro- and anti-apoptotic members of the BCL-2 family orchestrates the decision to undergo apoptosis. Beyond regulation of apoptosis, multiple BCL-2 proteins have recently emerged as active components of select homeostatic pathways carrying other cellular functions. This review focuses on BAD, which was the first BH3-only protein linked to proximal survival signals through phosphorylation by survival kinases. In addition to findings that delineated the physiological role of BAD in apoptosis and its dynamic regulation by phosphorylation, studies pointing to new roles for this protein in other physiological pathways, such as glucose metabolism, are highlighted. By executing its ‘day’ and ‘night’ jobs in metabolism and apoptosis, respectively, BAD helps coordinate mitochondrial fuel metabolism and the apoptotic machinery.
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References
Affaitati A, Cardone L, de Cristofaro T, Carlucci A, Ginsberg MD, Varrone S et al. (2003). Essential role of A-kinase anchor protein 121 for cAMP signaling to mitochondria. J Biol Chem 278: 4286–4294.
Amaravadi R, Thompson CB . (2005). The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 115: 2618–2624.
Andjelkovic M, Jakubowicz T, Cron P, Ming XF, Han JW, Hemmings BA . (1996). Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci USA 93: 5699–5704.
Arden C, Baltrusch S, Agius L . (2006). Glucokinase regulatory protein is associated with mitochondria in hepatocytes. FEBS Lett 580: 2065–2070.
Ayllon V, Martinez AC, Garcia A, Cayla X, Rebollo A . (2000). Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J 19: 2237–2246.
Balasubramanian R, Karve A, Kandasamy M, Meagher RB, Moore B . (2007). A role for F-actin in hexokinase-mediated glucose signaling. Plant Physiol 145: 1423–1434.
Beene DL, Scott JD . (2007). A-kinase anchoring proteins take shape. Curr Opin Cell Biol 19: 192–198.
Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM et al. (2007). Modulation of prostate cancer genetic risk by omega-3 and omega-6 fatty acids. J Clin Invest 117: 1866–1875.
Billen LP, Kokoski CL, Lovell JF, Leber B, Andrews DW . (2008). Bcl-XL inhibits membrane permeabilization by competing with Bax. PLoS Biol 6: e147.
Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ . (1995). Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 270: 2320–2326.
Blume-Jensen P, Janknecht R, Hunter T . (1998). The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr Biol 8: 779–782.
Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME . (1999). Cell survival promoted by the Ras–MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286: 1358–1362.
Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM . (2005). Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 54: 146–151.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.
Chattopadhyay A, Chiang CW, Yang E . (2001). BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest. Oncogene 20: 4507–4518.
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG et al. (2005). Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell 17: 393–403.
Chen Q, Lin RY, Rubin CS . (1997). Organelle-specific targeting of protein kinase AII (PKAII). Molecular and in situ characterization of murine A kinase anchor proteins that recruit regulatory subunits of PKAII to the cytoplasmic surface of mitochondria. J Biol Chem 272: 15247–15257.
Cheng WC, Berman SB, Ivanovska I, Jonas EA, Lee SJ, Chen Y et al. (2006). Mitochondrial factors with dual roles in death and survival. Oncogene 25: 4697–4705.
Chiang CW, Harris G, Ellig C, Masters SC, Subramanian R, Shenolikar S et al. (2001). Protein phosphatase 2A activates the proapoptotic function of BAD in interleukin- 3-dependent lymphoid cells by a mechanism requiring 14-3-3 dissociation. Blood 97: 1289–1297.
Chiang CW, Kanies C, Kim KW, Fang WB, Parkhurst C, Xie M et al. (2003). Protein phosphatase 2A dephosphorylation of phosphoserine 112 plays the gatekeeper role for BAD-mediated apoptosis. Mol Cell Biol 23: 6350–6362.
Chipuk JE, Green DR . (2008). How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol 18: 157–164.
Condorelli F, Salomoni P, Cotteret S, Cesi V, Srinivasula SM, Alnemri ES et al. (2001). Caspase cleavage enhances the apoptosis-inducing effects of BAD. Mol Cell Biol 21: 3025–3036.
Cotteret S, Jaffer ZM, Beeser A, Chernoff J . (2003). p21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Mol Cell Biol 23: 5526–5539.
Dan HC, Sun M, Kaneko S, Feldman RI, Nicosia SV, Wang HG et al. (2004). Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). J Biol Chem 279: 5405–5412.
Danial NN, Gramm CF, Scorrano L, Zhang CY, Krauss S, Ranger AM et al. (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424: 952–956.
Danial NN, Korsmeyer SJ . (2004). Cell death: critical control points. Cell 116: 205–219.
Danial NN, Walensky LD, Zhang CY, Choi CS, Fisher JK, Molina AJ et al. (2008). Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14: 144–153.
Datta SR, Brunet A, Greenberg ME . (1999). Cellular survival: a play in three Akts. Genes Dev 13: 2905–2927.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91: 231–241.
Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB et al. (2000). 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 6: 41–51.
Datta SR, Ranger AM, Lin MZ, Sturgill JF, Ma YC, Cowan CW et al. (2002). Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis. Dev Cell 3: 631–643.
De Rasmo D, Panelli D, Sardanelli AM, Papa S . (2008). cAMP-dependent protein kinase regulates the mitochondrial import of the nuclear encoded NDUFS4 subunit of complex I. Cell Signal 20: 989–997.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB . (2008). The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11–20.
del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . (1997). Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278: 687–689.
Deng H, Yu F, Chen J, Zhao Y, Xiang J, Lin A . (2008). Phosphorylation of Bad at Thr-201 by JNK1 promotes glycolysis through activation of phosphofructokinase-1. J Biol Chem 283: 20754–20760.
Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A . (2007). BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 12: 171–185.
Djouder N, Metzler SC, Schmidt A, Wirbelauer C, Gstaiger M, Aebersold R et al. (2007). S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling. Mol Cell 28: 28–40.
Eves EM, Xiong W, Bellacosa A, Kennedy SG, Tsichlis PN, Rosner MR et al. (1998). Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line. Mol Cell Biol 18: 2143–2152.
Fang X, Yu S, Eder A, Mao M, Bast Jr RC, Boyd D et al. (1999). Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18: 6635–6640.
Federici M, Hribal M, Perego L, Ranalli M, Caradonna Z, Perego C et al. (2001). High glucose causes apoptosis in cultured human pancreatic islets of Langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 50: 1290–1301.
Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB . (2003). The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Genes Dev 17: 1841–1854.
Freilinger A, Rosner M, Krupitza G, Nishino M, Lubec G, Korsmeyer SJ et al. (2006). Tuberin activates the proapoptotic molecule BAD. Oncogene 25: 6467–6479.
Freinkel N, Lewis NJ, Johnson R, Swenne I, Bone A, Hellerstrom C . (1984). Differential effects of age versus glycemic stimulation on the maturation of insulin stimulus-secretion coupling during culture of fetal rat islets. Diabetes 33: 1028–1038.
Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG et al. (2008). BAX activation is initiated at a novel interaction site. Nature 455: 1076–1081.
Gidday JM . (2006). Cerebral preconditioning and ischaemic tolerance. Nat Rev Neurosci 7: 437–448.
Giege P, Heazlewood JL, Roessner-Tunali U, Millar AH, Fernie AR, Leaver CJ et al. (2003). Enzymes of glycolysis are functionally associated with the mitochondrion in Arabidopsis cells. Plant Cell 15: 2140–2151.
Gilley J, Coffer PJ, Ham J . (2003). FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162: 613–622.
Gilmore AP, Valentijn AJ, Wang P, Ranger AM, Bundred N, O’Hare MJ et al. (2002). Activation of BAD by therapeutic inhibition of epidermal growth factor receptor and transactivation by insulin-like growth factor receptor. J Biol Chem 277: 27643–27650.
Giorgio M, Trinei M, Migliaccio E, Pelicci PG . (2007). Hydrogen peroxide: a metabolic by-product or a common mediator of ageing signals? Nat Rev Mol Cell Biol 8: 722–728.
Gnesutta N, Qu J, Minden A . (2001). The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. J Biol Chem 276: 14414–14419.
Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N . (2001). Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15: 1406–1418.
Gotz R, Wiese S, Takayama S, Camarero GC, Rossoll W, Schweizer U et al. (2005). Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nat Neurosci 8: 1169–1178.
Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ . (2001). p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98: 9666–9670.
Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS et al. (1999). Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell 3: 413–422.
Hardie DG . (2007). AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8: 774–785.
Hekman M, Albert S, Galmiche A, Rennefahrt UE, Fueller J, Fischer A et al. (2006). Reversible membrane interaction of BAD requires two C-terminal lipid binding domains in conjunction with 14-3-3 protein binding. J Biol Chem 281: 17321–17336.
Hettiarachchi KD, Zimmet PZ, Danial NN, Myers MA . (2008). Transplacental exposure to the vacuolar-ATPase inhibitor bafilomycin disrupts survival signaling in beta cells and delays neonatal remodeling of the endocrine pancreas. Exp Toxicol Pathol 60: 295–306.
Hickman JA, Hardwick JM, Kaczmarek LK, Jonas EA . (2008). Bcl-xL inhibitor ABT-737 reveals a dual role for Bcl-xL in synaptic transmission. J Neurophysiol 99: 1515–1522.
Hill DJ, Strutt B, Arany E, Zaina S, Coukell S, Graham CF . (2000). Increased and persistent circulating insulin-like growth factor II in neonatal transgenic mice suppresses developmental apoptosis in the pancreatic islets. Endocrinology 141: 1151–1157.
Hogg J, Hill DJ, Han VK . (1994). The ontogeny of insulin-like growth factor (IGF) and IGF-binding protein gene expression in the rat pancreas. J Mol Endocrinol 13: 49–58.
Houslay MD . (2006). A RSK(y) relationship with promiscuous PKA. Sci STKE 2006: pe32.
Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS . (1997). Identification of a novel protein kinase A anchoring protein that binds both type I and type II regulatory subunits. J Biol Chem 272: 8057–8064.
Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H . (2001). Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole- 4-carboxamide-1-beta-D-ribofuranoside, in a human hepatocellular carcinoma cell line. Biochem Biophys Res Commun 287: 562–567.
Janumyan YM, Sansam CG, Chattopadhyay A, Cheng N, Soucie EL, Penn LZ et al. (2003). Bcl-xL/Bcl-2 coordinately regulates apoptosis, cell cycle arrest and cell cycle entry. EMBO J 22: 5459–5470.
Jeong SY, Gaume B, Lee YJ, Hsu YT, Ryu SW, Yoon SH et al. (2004). Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers. EMBO J 23: 2146–2155.
Jetton TL, Lausier J, LaRock K, Trotman WE, Larmie B, Habibovic A et al. (2005). Mechanisms of compensatory beta-cell growth in insulin-resistant rats: roles of Akt kinase. Diabetes 54: 2294–2304.
Jonas EA, Hoit D, Hickman JA, Brandt TA, Polster BM, Fannjiang Y et al. (2003). Modulation of synaptic transmission by the BCL-2 family protein BCL-xL. J Neurosci 23: 8423–8431.
Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y et al. (2005). AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18: 283–293.
Kamer I, Sarig R, Zaltsman Y, Niv H, Oberkovitz G, Regev L et al. (2005). Proapoptotic BID is an ATM effector in the DNA-damage response. Cell 122: 593–603.
Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S et al. (2007). Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev 21: 1621–1635.
Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ . (2006). Role of Bax and Bak in mitochondrial morphogenesis. Nature 443: 658–662.
Kelekar A, Thompson CB . (1998). Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 8: 324–330.
Khor TO, Gul YA, Ithnin H, Seow HF . (2004). Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma. Cancer Lett 210: 139–150.
Kim BC, Mamura M, Choi KS, Calabretta B, Kim SJ . (2002). Transforming growth factor beta 1 induces apoptosis through cleavage of BAD in a Smad3-dependent mechanism in FaO hepatoma cells. Mol Cell Biol 22: 1369–1378.
Kim H, Rafiuddin-Shah M, Tu HC, Jeffers JR, Zambetti GP, Hsieh JJ et al. (2006). Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8: 1348–1358.
Kim MR, Jeong EG, Chae B, Lee JW, Soung YH, Nam SW et al. (2007). Pro-apoptotic PUMA and anti-apoptotic phospho-BAD are highly expressed in colorectal carcinomas. Dig Dis Sci 52: 2751–2756.
Kim WH, Lee JW, Suh YH, Hong SH, Choi JS, Lim JH et al. (2005). Exposure to chronic high glucose induces beta-cell apoptosis through decreased interaction of glucokinase with mitochondria: downregulation of glucokinase in pancreatic beta-cells. Diabetes 54: 2602–2611.
Konishi Y, Lehtinen M, Donovan N, Bonni A . (2002). Cdc2 phosphorylation of BAD links the cell cycle to the cell death machinery. Mol Cell 9: 1005–1016.
Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC et al. (2006). Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proc Natl Acad Sci USA 103: 14907–14912.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR et al. (2005). BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17: 525–535.
Labi V, Erlacher M, Kiessling S, Villunger A . (2006). BH3-only proteins in cell death initiation, malignant disease and anticancer therapy. Cell Death Differ 13: 1325–1338.
Leber B, Lin J, Andrews DW . (2007). Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis 12: 897–911.
Lee HY, Srinivas H, Xia D, Lu Y, Superty R, LaPushin R et al. (2003). Evidence that phosphatidylinositol 3-kinase- and mitogen-activated protein kinase kinase-4/c-Jun NH2-terminal kinase-dependent pathways cooperate to maintain lung cancer cell survival. J Biol Chem 278: 23630–23638.
Lee JW, Soung YH, Kim SY, Nam SW, Kim CJ, Cho YG et al. (2004). Inactivating mutations of proapoptotic Bad gene in human colon cancers. Carcinogenesis 25: 1371–1376.
Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . (2002). Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2: 183.
Levine B, Kroemer G . (2008). Autophagy in the pathogenesis of disease. Cell 132: 27–42.
Levine B, Sinha S, Kroemer G . (2008). Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy 4: 600–606.
Levine B, Yuan J . (2005). Autophagy in cell death: an innocent convict? J Clin Invest 115: 2679–2688.
Li H, Chen Y, Jones AF, Sanger RH, Collis LP, Flannery R et al. (2008). Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons. Proc Natl Acad Sci USA 105: 2169–2174.
Li H, Zhu H, Xu CJ, Yuan J . (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94: 491–501.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275: 1943–1947.
Li WQ, Jiang Q, Khaled AR, Keller JR, Durum SK . (2004a). Interleukin-7 inactivates the pro-apoptotic protein Bad promoting T cell survival. J Biol Chem 279: 29160–29166.
Li Z, Okamoto K, Hayashi Y, Sheng M . (2004b). The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119: 873–887.
Liadis N, Salmena L, Kwan E, Tajmir P, Schroer SA, Radziszewska A et al. (2007). Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models. Diabetes 56: 2302–2311.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M et al. (2007). The energy sensing LKB1–AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 9: 218–224.
Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G et al. (1998). Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 72: 8586–8596.
Ligon LA, Steward O . (2000). Role of microtubules and actin filaments in the movement of mitochondria in the axons and dendrites of cultured hippocampal neurons. J Comp Neurol 427: 351–361.
Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA et al. (2000). The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell 6: 1389–1399.
Liu W, Chin-Chance C, Lee EJ, Lowe Jr WL . (2002). Activation of phosphatidylinositol 3-kinase contributes to insulin-like growth factor I-mediated inhibition of pancreatic beta-cell death. Endocrinology 143: 3802–3812.
Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C et al. (2006). Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Mol Biol Cell 17: 263–271.
Lizcano JM, Morrice N, Cohen P . (2000). Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a novel site, Ser155. Biochem J 349: 547–557.
Lockshin RA, Zakeri Z . (2004). Apoptosis, autophagy, and more. Int J Biochem Cell Biol 36: 2405–2419.
Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T et al. (2005). Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 120: 237–248.
Luo X, Budihardjo I, Zou H, Slaughter C, Wang X . (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94: 481–490.
Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C et al. (2002). Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase-mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51: 1437–1442.
Macdonald A, Campbell DG, Toth R, McLauchlan H, Hastie CJ, Arthur JS . (2006). Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. BMC Cell Biol 7: 1.
Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P et al. (2007). Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 26: 2527–2539.
Mandal S, Guptan P, Owusu-Ansah E, Banerjee U . (2005). Mitochondrial regulation of cell cycle progression during development as revealed by the tenured mutation in Drosophila. Dev Cell 9: 843–854.
Marshall S . (2006). Role of insulin, adipocyte hormones, and nutrient-sensing pathways in regulating fuel metabolism and energy homeostasis: a nutritional perspective of diabetes, obesity, and cancer. Sci STKE 2006: re7.
Masters SC, Yang H, Datta SR, Greenberg ME, Fu H . (2001). 14-3-3 inhibits Bad-induced cell death through interaction with serine-136. Mol Pharmacol 60: 1325–1331.
Matschinsky FM, Magnuson MA, Zelent D, Jetton TL, Doliba N, Han Y et al. (2006). The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55: 1–12.
Miyawaki T, Mashiko T, Ofengeim D, Flannery RJ, Noh KM, Fujisawa S et al. (2008). Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons. Proc Natl Acad Sci USA 105: 4892–4897.
Mok CL, Gil-Gomez G, Williams O, Coles M, Taga S, Tolaini M et al. (1999). Bad can act as a key regulator of T cell apoptosis and T cell development. J Exp Med 189: 575–586.
Montanya E, Nacher V, Biarnes M, Soler J . (2000). Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy. Diabetes 49: 1341–1346.
Moore B, Zhou L, Rolland F, Hall Q, Cheng WH, Liu YX et al. (2003). Role of the Arabidopsis glucose sensor HXK1 in nutrient, light, and hormonal signaling. Science 300: 332–336.
Murata T, Katagiri H, Ishihara H, Shibasaki Y, Asano T, Toyoda Y et al. (1997). Co-localization of glucokinase with actin filaments. FEBS Lett 406: 109–113.
Ness JM, Harvey CA, Strasser A, Bouillet P, Klocke BJ, Roth KA . (2006). Selective involvement of BH3-only Bcl-2 family members Bim and Bad in neonatal hypoxia-ischemia. Brain Res 1099: 150–159.
Noshita N, Lewen A, Sugawara T, Chan PH . (2001). Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J Cereb Blood Flow Metab 21: 1442–1450.
Oberstein A, Jeffrey PD, Shi Y . (2007). Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 282: 13123–13132.
Obexer P, Geiger K, Ambros PF, Meister B, Ausserlechner MJ . (2007). FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell Death Differ 14: 534–547.
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA et al. (2005). An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435: 677–681.
Orrenius S, Zhivotovsky B, Nicotera P . (2003). Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4: 552–565.
Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G et al. (1997). Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. J Biol Chem 272: 30866–30872.
Owusu-Ansah E, Yavari A, Mandal S, Banerjee U . (2008). Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat Genet 40: 356–361.
Pastorino JG, Shulga N, Hoek JB . (2002). Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 277: 7610–7618.
Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122: 927–939.
Petrik J, Pell JM, Arany E, McDonald TJ, Dean WL, Reik W et al. (1999). Overexpression of insulin-like growth factor-II in transgenic mice is associated with pancreatic islet cell hyperplasia. Endocrinology 140: 2353–2363.
Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J et al. (2000). Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci 9: 2528–2534.
Pick A, Clark J, Kubstrup C, Levisetti M, Pugh W, Bonner-Weir S et al. (1998). Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 47: 358–364.
Pinton P, Rizzuto R . (2006). Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ 13: 1409–1418.
Pipeleers D, Kiekens R, Ling Z, Wilikens A, Schuit F . (1994). Physiologic relevance of heterogeneity in the pancreatic beta-cell population. Diabetologia 37 (Suppl 2): S57–S64.
Ranger AM, Zha J, Harada H, Datta SR, Danial NN, Gilmore AP et al. (2003). Bad-deficient mice develop diffuse large B cell lymphoma. Proc Natl Acad Sci USA 100: 9324–9329.
Reggiori F, Klionsky DJ . (2002). Autophagy in the eukaryotic cell. Eukaryot Cell 1: 11–21.
Robey RB, Hay N . (2006). Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25: 4683–4696.
Salomoni P, Condorelli F, Sweeney SM, Calabretta B . (2000). Versatility of BCR/ABL-expressing leukemic cells in circumventing proapoptotic BAD effects. Blood 96: 676–684.
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S et al. (2004). High frequency of mutations of the PIK3CA gene in human cancers. Science 304: 554.
Sastry KS, Karpova Y, Kulik G . (2006). Epidermal growth factor protects prostate cancer cells from apoptosis by inducing BAD phosphorylation via redundant signaling pathways. J Biol Chem 281: 27367–27377.
Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A et al. (2007). Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J Biol Chem 282: 14094–14100.
Scheid MP, Schubert KM, Duronio V . (1999). Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem 274: 31108–31113.
Schurmann A, Mooney AF, Sanders LC, Sells MA, Wang HG, Reed JC et al. (2000). p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol Cell Biol 20: 453–461.
Seo SY, Chen YB, Ivanovska I, Ranger AM, Hong SJ, Dawson VL et al. (2004). BAD is a pro-survival factor prior to activation of its pro-apoptotic function. J Biol Chem 279: 42240–42249.
She QB, Solit DB, Ye Q, O’Reilly KE, Lobo J, Rosen N . (2005). The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell 8: 287–297.
Smith WE, Langer S, Wu C, Baltrusch S, Okar DA . (2007). Molecular coordination of hepatic glucose metabolism by the 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase:glucokinase complex. Mol Endocrinol 21: 1478–1487.
Soderling SH, Guire ES, Kaech S, White J, Zhang F, Schutz K et al. (2007). A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory. J Neurosci 27: 355–365.
Sone H, Kagawa Y . (2005). Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice. Diabetologia 48: 58–67.
Sung JY, Engmann O, Teylan MA, Nairn AC, Greengard P, Kim Y . (2008). WAVE1 controls neuronal activity-induced mitochondrial distribution in dendritic spines. Proc Natl Acad Sci USA 105: 3112–3116.
Tan Y, Demeter MR, Ruan H, Comb MJ . (2000). BAD Ser-155 phosphorylation regulates BAD/Bcl-XL interaction and cell survival. J Biol Chem 275: 25865–25869.
Taylor SS, Yang J, Wu J, Haste NM, Radzio-Andzelm E, Anand G . (2004). PKA: a portrait of protein kinase dynamics. Biochim Biophys Acta 1697: 259–269.
Terauchi Y, Takamoto I, Kubota N, Matsui J, Suzuki R, Komeda K et al. (2007). Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance. J Clin Invest 117: 246–257.
Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD, Walzer G et al. (2008). Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27: 433–446.
Uzgare AR, Isaacs JT . (2004). Enhanced redundancy in Akt and mitogen-activated protein kinase-induced survival of malignant versus normal prostate epithelial cells. Cancer Res 64: 6190–6199.
Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB . (2001). Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21: 5899–5912.
Virdee K, Parone PA, Tolkovsky AM . (2000). Phosphorylation of the pro-apoptotic protein BAD on serine 155, a novel site, contributes to cell survival. Curr Biol 10: 1151–1154.
von Gise A, Lorenz P, Wellbrock C, Hemmings B, Berberich-Siebelt F, Rapp UR et al. (2001). Apoptosis suppression by Raf-1 and MEK1 requires MEK- and phosphatidylinositol 3-kinase-dependent signals. Mol Cell Biol 21: 2324–2336.
Waingeh VF, Gustafson CD, Kozliak EI, Lowe SL, Knull HR, Thomasson KA . (2006). Glycolytic enzyme interactions with yeast and skeletal muscle F-actin. Biophys J 90: 1371–1384.
Walensky LD, Pitter K, Morash J, Oh KJ, Barbuto S, Fisher J et al. (2006). A stapled BID BH3 helix directly binds and activates BAX. Mol Cell 24: 199–210.
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F et al. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284: 339–343.
Wang HG, Rapp UR, Reed JC . (1996a). Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell 87: 629–638.
Wang HG, Takayama S, Rapp UR, Reed JC . (1996b). Bcl-2 interacting protein, BAG-1, binds to and activates the kinase Raf-1. Proc Natl Acad Sci USA 93: 7063–7068.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ et al. (2001). Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730.
Westphal RS, Soderling SH, Alto NM, Langeberg LK, Scott JD . (2000). Scar/WAVE-1, a Wiskott–Aldrich syndrome protein, assembles an actin- associated multi-kinase scaffold. EMBO J 19: 4589–4600.
Wiederkehr A, Wollheim CB . (2006). Minireview: implication of mitochondria in insulin secretion and action. Endocrinology 147: 2643–2649.
Wiese S, Pei G, Karch C, Troppmair J, Holtmann B, Rapp UR et al. (2001). Specific function of B-Raf in mediating survival of embryonic motoneurons and sensory neurons. Nat Neurosci 4: 137–142.
Wikstrom JD, Katzman SM, Mohamed H, Twig G, Graf SA, Heart E et al. (2007). Beta-cell mitochondria exhibit membrane potential heterogeneity that can be altered by stimulatory or toxic fuel levels. Diabetes 56: 2569–2578.
Wilson JE . (2003). Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 206: 2049–2057.
Wu L, Nicholson W, Knobel SM, Steffner RJ, May JM, Piston DW et al. (2004). Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines. J Biol Chem 279: 12126–12134.
Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ et al. (2003). The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem 278: 45358–45367.
Yano S, Morioka M, Fukunaga K, Kawano T, Hara T, Kai Y et al. (2001). Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus. J Cereb Blood Flow Metab 21: 351–360.
Youle RJ, Strasser A . (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9: 47–59.
Yu C, Minemoto Y, Zhang J, Liu J, Tang F, Bui TN et al. (2004). JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell 13: 329–340.
Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ . (1997). BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J Biol Chem 272: 24101–24104.
Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ . (1996). Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87: 619–628.
Zhou XM, Liu Y, Payne G, Lutz RJ, Chittenden T . (2000a). Growth factors inactivate the cell death promoter BAD by phosphorylation of its BH3 domain on Ser155. J Biol Chem 275: 25046–25051.
Zhou YP, Pena JC, Roe MW, Mittal A, Levisetti M, Baldwin AC et al. (2000b). Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion. Am J Physiol Endocrinol Metab 278: E340–E351.
Zinkel S, Gross A, Yang E . (2006). BCL2 family in DNA damage and cell cycle control. Cell Death Differ 13: 1351–1359.
Zinkel SS, Hurov KE, Ong C, Abtahi FM, Gross A, Korsmeyer SJ . (2005). A role for proapoptotic BID in the DNA-damage response. Cell 122: 579–591.
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I thank Eric Smith for editorial assistance and the creation of figures.
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Danial, N. BAD: undertaker by night, candyman by day. Oncogene 27 (Suppl 1), S53–S70 (2008). https://doi.org/10.1038/onc.2009.44
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