| Description | 168 amino acids, 18,4 kDa.; 'BH3 only' Bcl2 family member (do not possess BH1, 2 and 4 domains). The BH3 domain is essential for proapoptotic function. There is structural similarities between the Bcl2 family proteins and bacterial toxins which form membrane pores after oligomerisation. Do not possess a transmembrane domain in COOH term, in contrast with a number of other BCL2 family members; may be phosphorylated on serine residues (see below). |
| Expression | wide |
| Localisation | cytoplasm vs membrane of the mitochondria (see below) |
| Function | Proapoptotic protein:
In its inactive form, Bad is phosphorylated. Proteins which phosphorylate BAD are: RAF1, ribosomal S6 kinase 1 (p90/RSK1), AKT/PKB (PI3K-AKT pathway) at Serine 136 (in murine BAD), PKA at Ser 155, PIM1and PIM2 at Ser 112 (Ser 75, 99, and 118 in human BAD correspond to Ser 112, 136, and 155 in murine BAD respectively). Phosphorylated BAD interacts with 14-3-3 scaffold proteins in the cytoplasm (14-3-3 is a protein which can interact with a hundred other proteins). Cleavage of the 14-3-3 protein by caspase-3 allows the release of BAD from its association with the 14-3-3 protein and facilitates BAD translocation from the cytosol to the mitochondria. Under apoptotic stimuli also, calcineurin (Ca++ activated protein phosphatase) dephosphorylates BAD, also allowing its dissociation from 14-3-3. Once BAD is dephosphorylated (posttranslational modification), it is active; it translocates to the outer membrane of the mitochondria (like other proapototic members of the Bcl2 family), and forms heterodimers with BCL-XL (and, to a lesser extend, heterodimers with BCL2 or BCL2L2) to block BCL-XL antiapoptotic function. Dimers BCL-XL /BAD are similar to dimers BCL-XL /BAK |
| Homology | Bcl2 family members:
The antiapoptotic members with BH 1 to 4 domains: BCL2 (18q21), BCL1L1/BCLX-L ID: n129> (20q11), BCL2L2/BCL-W (14q11), BCL1L10/BCL-B/BOO/DIVA (15q21), BCL2A1/BFL1/A1 (15q24), BNIP1/EIB-19K (5q33), (1q21) The proapoptotic members with BH 1 to 3 domains: BAK1/BCL2L7 (6p21), BAX (19q13), BCL2L13/BCL-Rambo/MIL1 ID: n236> (22q11), (2q37) The only-BH3 apoptotic members: BBC3/PUMA (19q13), BCL2L11/BIM/BOD (2q13), BID (22q11), BIK/NBK/BBC1 (22q13), BLK (8p23), BMF (15q14), BNIP3/NIP3 (10q26), BMIP3L/NIX (8p21), HRK/DP5/BID3 (12q24), PMAIP1/NOXA (18q21) |
| Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. |
| Adachi M, Zhang YB, Imai K |
| FEBS letters. 2003 ; 551 (1-3) : 147-152. |
| PMID 12965220 |
| |
| Control of proliferation by Bcl-2 family members. |
| Bonnefoy-Berard N, Aouacheria A, Verschelde C, Quemeneur L, Marçais A, Marvel J |
| Biochimica et biophysica acta. 2004 ; 1644 (2-3) : 159-168. |
| PMID 14996500 |
| |
| Role of PI3-kinase-dependent Bad phosphorylation and altered transcription in cytokine-mediated neutrophil survival. |
| Cowburn AS, Cadwallader KA, Reed BJ, Farahi N, Chilvers ER |
| Blood. 2002 ; 100 (7) : 2607-2616. |
| PMID 12239175 |
| |
| 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. |
| Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME |
| Molecular cell. 2000 ; 6 (1) : 41-51. |
| PMID 10949026 |
| |
| Bad is a BH3 domain-containing protein that forms an inactivating dimer with Bcl-XL. |
| Kelekar A, Chang BS, Harlan JE, Fesik SW, Thompson CB |
| Molecular and cellular biology. 1997 ; 17 (12) : 7040-7046. |
| PMID 9372935 |
| |
| Induction of Bad-mediated apoptosis by Sindbis virus infection: involvement of pro-survival members of the Bcl-2 family. |
| Moriishi K, Koura M, Matsuura Y |
| Virology. 2002 ; 292 (2) : 258-271. |
| PMID 11878929 |
| |
| Dimerization properties of human BAD. Identification of a BH-3 domain and analysis of its binding to mutant BCL-2 and BCL-XL proteins. |
| Ottilie S, Diaz JL, Horne W, Chang J, Wang Y, Wilson G, Chang S, Weeks S, Fritz LC, Oltersdorf T |
| The Journal of biological chemistry. 1997 ; 272 (49) : 30866-30872. |
| PMID 9388232 |
| |
| Structural biology of the Bcl-2 family of proteins. |
| Petros AM, Olejniczak ET, Fesik SW |
| Biochimica et biophysica acta. 2004 ; 1644 (2-3) : 83-94. |
| PMID 14996493 |
| |
| Bcl-2 family members: integrators of survival and death signals in physiology and pathology [corrected]. |
| Schinzel A, Kaufmann T, Borner C |
| Biochimica et biophysica acta. 2004 ; 1644 (2-3) : 95-105. |
| PMID 14996494 |
| |
| Bcl-2 family members and disease. |
| Sorenson CM |
| Biochimica et biophysica acta. 2004 ; 1644 (2-3) : 169-177. |
| PMID 14996501 |
| |
| Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. |
| Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC |
| Science (New York, N.Y.). 1999 ; 284 (5412) : 339-343. |
| PMID 10195903 |
| |
| Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis. |
| Won J, Kim DY, La M, Kim D, Meadows GG, Joe CO |
| The Journal of biological chemistry. 2003 ; 278 (21) : 19347-19351. |
| PMID 12657644 |
| |
| The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. |
| Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ, Lilly M |
| The Journal of biological chemistry. 2003 ; 278 (46) : 45358-45367. |
| PMID 12954615 |
| |
| Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. |
| Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ |
| Cell. 1995 ; 80 (2) : 285-291. |
| PMID 7834748 |
| |
| Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. |
| del Peso L, Gonz´lez-Garcí M, Page C, Herrera R, Nuñez G |
| Science (New York, N.Y.). 1997 ; 278 (5338) : 687-689. |
| PMID 9381178 |
| |
