Bcl-2-associated death promoter explained

Symbol:	Bcl-2_BAD
Pro-apoptotic Bcl-2 protein, BAD
Pfam:	PF10514
Interpro:	IPR018868

The BCL2 associated agonist of cell death^[1] (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family,^[2] a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family.^[3] After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

Mechanism of action

Bax/Bak are believed to initiate apoptosis by forming a pore in the mitochondrial outer membrane that allows cytochrome c to escape into the cytoplasm and activate the pro-apoptotic caspase cascade. The anti-apoptotic Bcl-2 and Bcl-xL proteins inhibit cytochrome c release through the mitochondrial pore and also inhibit activation of the cytoplasmic caspase cascade by cytochrome c.^[4]

Dephosphorylated BAD forms a heterodimer with Bcl-2 and Bcl-xL, inactivating them and thus allowing Bax/Bak-triggered apoptosis. When BAD is phosphorylated by Akt/protein kinase B (triggered by PIP₃), it forms the BAD-(14-3-3) protein heterodimer. This leaves Bcl-2 free to inhibit Bax-triggered apoptosis.^[5] BAD phosphorylation is thus anti-apoptotic, and BAD dephosphorylation (e.g., by Ca²⁺-stimulated Calcineurin) is pro-apoptotic. The latter may be involved in neural diseases such as schizophrenia.^[6]

Interactions

Bcl-2-associated death promoter has been shown to interact with:

• BCL2L1^{[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]}
• BCL2A1^[7]
• BCL2L2^{[7] [11] [18] [19]}
• Bcl-2^{[7] [13]}
• MCL1^{[7] [18]}
• S100A10
• YWHAQ^{[7] [20]} and
• YWHAZ^[21]

See also

• Programmed cell death

Further reading

• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M . HIV/SIV escape from immune surveillance: focus on Nef . Curr. HIV Res. . 2 . 2 . 141–51 . 2004 . 15078178 . 10.2174/1570162043484924 .
• Jiang P, Du W, Wu M . p53 and Bad: remote strangers become close friends . Cell Res. . 17 . 4 . 283–5 . 2007 . 17404594 . 10.1038/cr.2007.19 . free .
• Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ . Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death . Cell . 80 . 2 . 285–91 . 1995 . 7834748 . 10.1016/0092-8674(95)90411-5 . 10343291 . free .
• Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ . Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L) . Cell . 87 . 4 . 619–28 . 1996 . 8929531 . 10.1016/S0092-8674(00)81382-3 . 860908 . free .
• Wang HG, Rapp UR, Reed JC . Bcl-2 targets the protein kinase Raf-1 to mitochondria . Cell . 87 . 4 . 629–38 . 1996 . 8929532 . 10.1016/S0092-8674(00)81383-5 . 16559750 . free .
• Inohara N, Ding L, Chen S, Núñez G . harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L) . EMBO J. . 16 . 7 . 1686–94 . 1997 . 9130713 . 1169772 . 10.1093/emboj/16.7.1686 .
• Zha J, Harada H, Osipov K, Jockel J, Waksman G, Korsmeyer SJ . BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity . J. Biol. Chem. . 272 . 39 . 24101–4 . 1997 . 9305851 . 10.1074/jbc.272.39.24101 . free .
• Hsu SY, Kaipia A, Zhu L, Hsueh AJ . Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 . Mol. Endocrinol. . 11 . 12 . 1858–67 . 1997 . 10.1210/mend.11.12.0023 . 9369453 . free .
• del Peso L, González-García M, Page C, Herrera R, Nuñez G . Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt . Science . 278 . 5338 . 687–9 . 1997 . 9381178 . 10.1126/science.278.5338.687 . 1997Sci...278..687D .
• Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC, Oltersdorf T . 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 . 49 . 30866–72 . 1997 . 9388232 . 10.1074/jbc.272.49.30866 . free .
• Huang DC, Adams JM, Cory S . The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4 . EMBO J. . 17 . 4 . 1029–39 . 1998 . 9463381 . 1170452 . 10.1093/emboj/17.4.1029 .
• Blume-Jensen P, Janknecht R, Hunter T . The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136 . Curr. Biol. . 8 . 13 . 779–82 . 1998 . 9651683 . 10.1016/S0960-9822(98)70302-1 . 15596347 . free . 1998CBio....8..779B .
• Strobel T, Tai YT, Korsmeyer S, Cannistra SA . BAD partly reverses paclitaxel resistance in human ovarian cancer cells . Oncogene . 17 . 19 . 2419–27 . 1998 . 9824152 . 10.1038/sj.onc.1202180 . free .
• Song Q, Kuang Y, Dixit VM, Vincenz C . Boo, a novel negative regulator of cell death, interacts with Apaf-1 . EMBO J. . 18 . 1 . 167–78 . 1999 . 9878060 . 1171112 . 10.1093/emboj/18.1.167 .
• Yasuda M, Han JW, Dionne CA, Boyd JM, Chinnadurai G . BNIP3alpha: a human homolog of mitochondrial proapoptotic protein BNIP3 . Cancer Res. . 59 . 3 . 533–7 . 1999 . 9973195 .
• Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC . Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD . Science . 284 . 5412 . 339–43 . 1999 . 10195903 . 10.1126/science.284.5412.339 . 1999Sci...284..339W .
• Holmgreen SP, Huang DC, Adams JM, Cory S . Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members . Cell Death Differ. . 6 . 6 . 525–32 . 1999 . 10381646 . 10.1038/sj.cdd.4400519 . free .
• Ostrerova N, Petrucelli L, Farrer M, Mehta N, Choi P, Hardy J, Wolozin B . Benjamin Wolozin . alpha-Synuclein shares physical and functional homology with 14-3-3 proteins . J. Neurosci. . 19 . 14 . 5782–91 . 1999 . 10407019 . 10.1523/JNEUROSCI.19-14-05782.1999. 6783081 . free .
• Scheid MP, Schubert KM, Duronio V . Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase . J. Biol. Chem. . 274 . 43 . 31108–13 . 1999 . 10521512 . 10.1074/jbc.274.43.31108 . free .
• Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME . Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms . Science . 286 . 5443 . 1358–62 . 1999 . 10558990 . 10.1126/science.286.5443.1358 .

Notes and References

1. Web site: BAD BCL2 associated agonist of cell death [Homo sapiens (Human)] - Gene - NCBI.
2. Adachi M, Imai K . The proapoptotic BH3-only protein BAD transduces cell death signals independently of its interaction with Bcl-2 . Cell Death Differ. . 9 . 11 . 1240–7 . 2002 . 12404123 . 10.1038/sj.cdd.4401097 . free .
3. Hsu SY, Kaipia A, Zhu L, Hsueh AJ . Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 . Mol. Endocrinol. . 11 . 12 . 1858–67 . 1997 . 10.1210/mend.11.12.0023 . 9369453 . free .
4. Helmreich, E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 238-43
5. E.J.M. (2001) The Biochemistry of Cell Signalling, pp. 242
6. Foster, T.C. et al. (2001) J. Neurosci. 21, 4066-4073, "Calcineurin Links Ca++ Dysregulation with Brain Aging"(
7. Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC . Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function . Mol. Cell . 17 . 3 . 393–403 . February 2005 . 15694340 . 10.1016/j.molcel.2004.12.030 . free .
8. Jin Z, Xin M, Deng X . Survival function of protein kinase C as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-activated bad kinase . J. Biol. Chem. . 280 . 16 . 16045–52 . April 2005 . 15705582 . 10.1074/jbc.M413488200 . free .
9. Strobel T, Tai YT, Korsmeyer S, Cannistra SA . BAD partly reverses paclitaxel resistance in human ovarian cancer cells . Oncogene . 17 . 19 . 2419–27 . November 1998 . 9824152 . 10.1038/sj.onc.1202180 . free .
10. Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M . Development of a high-throughput fluorescence polarization assay for Bcl-x(L) . Anal. Biochem. . 307 . 1 . 70–5 . August 2002 . 12137781 . 10.1016/S0003-2697(02)00028-3 .
11. Ayllón V, Cayla X, García A, Fleischer A, Rebollo A . The anti-apoptotic molecules Bcl-xL and Bcl-w target protein phosphatase 1alpha to Bad . Eur. J. Immunol. . 32 . 7 . 1847–55 . July 2002 . 12115603 . 10.1002/1521-4141(200207)32:7<1847::AID-IMMU1847>3.0.CO;2-7 . free .
12. Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG . Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis . Nat. Cell Biol. . 2 . 1 . 1–6 . January 2000 . 10620799 . 10.1038/71316 . 52847351 .
13. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ . Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death . Cell . 80 . 2 . 285–91 . January 1995 . 7834748 . 10.1016/0092-8674(95)90411-5 . 10343291 . free .
14. Petros AM, Nettesheim DG, Wang Y, Olejniczak ET, Meadows RP, Mack J, Swift K, Matayoshi ED, Zhang H, Thompson CB, Fesik SW . Rationale for Bcl-xL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies . Protein Sci. . 9 . 12 . 2528–34 . Dec 2000 . 11206074 . 2144516 . 10.1110/ps.9.12.2528 .
15. Chattopadhyay A, Chiang CW, Yang E . BAD/BCL-[X(L)] heterodimerization leads to bypass of G0/G1 arrest . Oncogene . 20 . 33 . 4507–18 . July 2001 . 11494146 . 10.1038/sj.onc.1204584 . free .
16. Iwahashi H, Eguchi Y, Yasuhara N, Hanafusa T, Matsuzawa Y, Tsujimoto Y . Synergistic anti-apoptotic activity between Bcl-2 and SMN implicated in spinal muscular atrophy . Nature . 390 . 6658 . 413–7 . November 1997 . 9389483 . 10.1038/37144 . 1997Natur.390..413I . 1936633 .
17. Komatsu K, Wharton W, Hang H, Wu C, Singh S, Lieberman HB, Pledger WJ, Wang HG . PCNA interacts with hHus1/hRad9 in response to DNA damage and replication inhibition . Oncogene . 19 . 46 . 5291–7 . November 2000 . 11077446 . 10.1038/sj.onc.1203901 . free .
18. Bae J, Hsu SY, Leo CP, Zell K, Hsueh AJ . Underphosphorylated BAD interacts with diverse antiapoptotic Bcl-2 family proteins to regulate apoptosis . Apoptosis . 6 . 5 . 319–30 . October 2001 . 11483855 . 10.1023/A:1011319901057 . 23119757 .
19. Holmgreen SP, Huang DC, Adams JM, Cory S . Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members . Cell Death Differ. . 6 . 6 . 525–32 . June 1999 . 10381646 . 10.1038/sj.cdd.4400519 . free .
20. Hsu SY, Kaipia A, Zhu L, Hsueh AJ . Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11 . Mol. Endocrinol. . 11 . 12 . 1858–67 . November 1997 . 10.1210/mend.11.12.0023 . 9369453 . free .
21. Yang H, Masters SC, Wang H, Fu H . The proapoptotic protein Bad binds the amphipathic groove of 14-3-3zeta . Biochim. Biophys. Acta . 1547 . 2 . 313–9 . June 2001 . 11410287 . 10.1016/S0167-4838(01)00202-3 .