BAK1 (BCL2-antagonist/killer 1)

2010-02-01   Grant Dewson , Ruth Kluck 

The Walter, Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Melbourne, Australia





The BAK1 gene, with 7748 bases in length, and contains 6 exons. The first exon is non-coding, and most of the largest, final exon is untranslated.


The BAK1 gene transcribes a 211 aa protein Bak. A possible 101 aa splice variant, called BAK-like, contains BH1, BH2 and TM domains, but no BH3 domain, with a 2.4 kb transcript of BAK-like detected in most human tissues and exhibiting pro-apoptotic activity. Two other human BAK1 mRNA variants are present in GenBak but may not be expressed: the BakM variant would be 190 aa and lack 21 amino acids in the linker region between alpha-helices 1 and 2; another would be 153 aa with the stop codon upstream of a splice junction and therefore predicted to be subject to nonsense-mediated mRNA decay. However in mice, a similar 151 aa N-Bak that contains only the BH3 domain is reportedly expressed in neurons.


There are two pseudogenes: Bak2 (chromosome 20) and Bak3 (chromosome 11).



The BAK1 gene encodes for a 23409 Da protein, named Bak. The Bak cDNA was isolated by three groups by virtue of its protein product interacting with the adenovirus E1B 19K protein, or its homology to the BH1 and BH2 domains of Bcl-2. The BH3 domain of Bak is essential for its binding to a hydrophobic surface groove on the prosurvival proteins Bcl-xL and Mcl-1. The Bak BH3 domain is also important for binding to a similar hydrophobic groove in another activated Bak molecule to form Bak oligomers and the formation of pores.
Atlas Image
The human Bak protein is 211 aa in length. Bcl-2 homology (BH) domains indicate regions of sequence homology with other Bcl-2 family members, with the BH3 domain being present in all members. The structure of non-activated Bak is similar to that of the prosurvival Bcl-2 family members, with alpha helices 1-9 indicated. The oligomerization domain is important for homo-oligomerization and pore formation, while the transmembrane domain anchors Bak in the mitochondrial outer membrane.


BAK1 mRNA is expressed widely in different tissues as an approximately 2.4 kb transcript. Highest mRNA levels are in the heart and skeletal muscle.


The Bak protein is inserted in the mitochondrial outer membrane in healthy cells, while its close homologue Bax translocates to mitochondria after an apoptotic stimulus. A small proportion of Bak has also been detected at the endoplasmic reticulum membrane.


Bak (or Bax) is required to form pores in the mitochondrial outer membrane during apoptotic cell death. The killing activity of Bak is regulated by other members of the Bcl-2 family. For example, certain BH3-only proteins (Bim and Bid) are reported to directly bind Bak to convert it into the activated conformation, while the prosurvival proteins (e.g. Bcl-xL and Mcl-1) can sequester activated Bak and so prevent Bak homo-oligomerization and pore formation. The role of Bak at the ER membrane is unclear.


Human Bak shares 99.5% amino acid identity with Pan troglodytes, 91.9% identity with Canis lupus familiaris, 86.2% with Bos taurus, 77.2% with Rattus norvegicus. BAK1 is not found in the Danio rerio genome. Human Bak has 53% amino-acid sequence identity with the BH1 and BH2 domains of Bcl-2. Over the full sequence, Bak is 25, 33 and 19% identical to Bcl-2, Bcl-xL and Bax, respectively.



Several Bak single point mutations have been associated with autoimmune diseases, aortic aneurysms, and cervical, colorectal and gastric cancers, although the causal relationship is not clear. In addition, around 200 SNPs, with unknown clinical association have been reported in Entrez SNP database.


Somatic mutations were increased in uterine cervical carcinoma (6 from 42) compared with non-neoplastic tissue (0 from 32). While an early study reported somatic mutations in 17% of samples of colorectal and gastric cancers in Korean patients, a later study reported no somatic mutations in 192 colorectal and gastric cancers.

Implicated in

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Lymphoma and leukemia
Lymphomas and leukemias have high levels of Bcl-2 prosurvival proteins that prevent Bak (and Bax) from inducing apoptosis. New anti-cancer therapies that target prosurvival proteins can activate Bak (or Bax) to re-instate apoptotic cell death. In one example, a new drug, GX15-070, was found to induce apoptosis in mantle cell lymphoma cell lines by binding to Mcl-1 and assist in Bak activation (Pérez-Galán et al., 2007). This drug is in clinical trials for refractory chronic lymphocytic leukemia (Storey, 2008), and is presumably acting by indirectly activating Bak (or Bax).
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Gastric and colorectal cancer
The first report of Bak mutations being associated with gastrointestinal cancers was of missense BAK1 mutations in 3 of 24 gastric cancers and 2 of 20 colorectal cancers, with mutations observed only in advanced-stage cancers (Kondo et al., 2000). In another study, BAK1 mutations were also rare (3/107) in patients with gastric adenocarcinomas, and were each associated with late stage disease (Kim et al., 2003). However, no somatic mutations were found in 192 patients with colorectal and gastric cancers, and the rare single-nucleotide substitutions (4/129) were also found in the corresponding normal tissue samples (Sakamoto et al., 2004).
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Uterine cervical carcinoma
Possible role for Bak mutation in uterine cervical carcinoma was reported (Wani et al., 2003). In a study of 42 patients, 6 missense (M60V, D30N, D57N, V74M, I80T and V191A) and one silent mutations in the coding region of BAK1 were found, with no mutations detected in 32 non-neoplastic cervix tissue samples. Mutations were associated with late-stage disease and with resistance to chemotherapy, but were not statistically significant due to sample size.
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In patients with superficial-spreading melanoma high Bak levels corresponded to improved survival (10-year survival of 62%), while low Bak correlated with low survival (10-year survival of 10%) (Fecker et al., 2006). Bax levels correlated in a similar way.
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Autoimmune diseases
Severe autoimmune disease occurs in adult mice following deletion of both Bak and its close relative Bax (Takeuchi et al., 2005). The mice accumulate excess memory B- and T-cells in lymphoid and mesenchymal organs, leading to hepato-splenomegaly, lymphadenopathy, and thymic selection impairment. In humans, similar deletion of two copies of BAK1 (and BAX) does not occur, however less marked changes in Bak protein levels, as well as BAK1 mutations, have been associated with autoimmune disease in rare cases (see below).
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Sjogrens syndrome
The Bak protein and its gene mutation may participate in the pathology and susceptibility of Sjogrens syndrome, as Bak was over-expressed in patient autoimmune lesions (Anaya et al., 2005). In a later study three polymorphisms in BAK1 were associated with Sjogrens syndrome (Delgado-Vega et al., 2009).
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Coeliac disease
A significant increase in Bak mRNA and protein levels was found in the intestinal lesions of patients with untreated coeliac disease (Chernavsky et al., 2002). The increase in Bak and in apoptosis of enterocytes may be due to increased IFN-gamma signalling.
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Graves disease
Differential expression of Bak (and Bcl-2 and Bax) was associated with apoptosis in thyrocytes and lymphoid follicles, implicating Bak in the pathology of Graves disease (Hiromatsu et al., 2004).
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Multiple sclerosis
Bak mRNA levels were increased in the autoimmune lesions of patients with multiple sclerosis (Banisor and Kalman, 2004).
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Ataxia telangiectasia
BAK1 mutations were observed in 8 of 50 patients with ataxia telangiectasia, and were each a silent mutation in exon 2 in codon 14 (TGC>TGT), while none of the healthy controls had such an alteration (Isaian et al., 2009).
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Transient platelet loss
Bak can be activated to kill platelets as a side effect of new anti-cancer treatments (Mason et al., 2007; Oltersdorf et al., 2005). The small molecule ABT-737 is a BH3-mimetic that binds specifically to prosurvival proteins (Bcl-2, Bcl-xL, Bcl-w) that are commonly over-expressed in cancers. As platelets contain Bcl-xL as the predominant prosurvival protein guarding Bak, ABT-737 causes Bak activation and transient loss of platelets.
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Age-related hearing loss
In mice, Bak-mediated apoptosis exacerbated age-related hearing loss (Someya et al., 2009; Someya et al., 2007). Moreover, hearing loss was decreased if Bak was deleted, if mice were kept on a calorie restriction diet, or given oral supplementation with antioxidants. In keeping with oxidative stress was proposed to induce Bak expression in primary cells from cochlear cells.
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Aortic aneurysms
A possible role for Bak mutation in aortic aneurysms was evident in a study of 31 patients with abdominal aortic aneurysms (Gottlieb et al., 2009). Two single nucleotide polymorphisms (R42H and V52A) in the BAK1 gene were present in both diseased (31 cases) and healthy aortic tissue (5 cases), but not in matching blood samples. The authors propose that multiple variants of a gene such as BAK1 might pre-exist within disease-susceptible tissues, and can be selected for during disease progression.


Pubmed IDLast YearTitleAuthors
158465892005Immunogenetics of primary Sjögren's syndrome in Colombians.Anaya JM et al
160935672005Phylogenomics of life-or-death switches in multicellular animals: Bcl-2, BH3-Only, and BNip families of apoptotic regulators.Aouacheria A et al
151247642004Bcl-2 and its homologues in the brain of patients with multiple sclerosis.Banisor I et al
119087042002Evidences of the involvement of Bak, a member of the Bcl-2 family of proteins, in active coeliac disease.Cherñavsky AC et al
77157301995Induction of apoptosis by the Bcl-2 homologue Bak.Chittenden T et al
192823072010Bcl-2 antagonist killer 1 (BAK1) polymorphisms influence the risk of developing autoimmune rheumatic diseases in women.Delgado-Vega AM et al
197955252009Mechanisms by which Bak and Bax permeabilise mitochondria during apoptosis.Dewson G et al
199418282009Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices.Dewson G et al
165283642006Loss of proapoptotic Bcl-2-related multidomain proteins in primary melanomas is associated with poor prognosis.Fecker LF et al
195140602009BAK1 gene variation and abdominal aortic aneurysms.Gottlieb B et al
95733421998Genomic structure and domain organisation of the human Bak gene.Herberg JA et al
166450942006RETRACTED: Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1alpha.Hetz C et al
153517962004Immunohistochemical analysis of bcl-2, Bax and Bak expression in thyroid glands from patients with Graves' disease.Hiromatsu Y et al
198989282010BAK, BAX, and NBK/BIK proapoptotic gene alterations in Iranian patients with ataxia telangiectasia.Isaian A et al
170359962006Role of Bax and Bak in mitochondrial morphogenesis.Karbowski M et al
77157311995Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak.Kiefer MC et al
150035052004Enhanced apoptosis by a novel gene, Bak-like, that lacks the BH3 domain.Kim JK et al
127675162003Mutations of the BAK gene are infrequent in advanced gastric adenocarcinomas in Koreans.Kim SP et al
109697702000Mutations of the bak gene in human gastric and colorectal cancers.Kondo S et al
111632122000The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues.Lindsten T et al
173828852007Programmed anuclear cell death delimits platelet life span.Mason KD et al
159022082005An inhibitor of Bcl-2 family proteins induces regression of solid tumours.Oltersdorf T et al
172278352007The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.Pérez-Galán P et al
146549702004Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers.Sakamoto I et al
199013382009Age-related hearing loss in C57BL/6J mice is mediated by Bak-dependent mitochondrial apoptosis.Someya S et al
168903262007Caloric restriction suppresses apoptotic cell death in the mammalian cochlea and leads to prevention of presbycusis.Someya S et al
190434472008Targeting apoptosis: selected anticancer strategies.Storey S et al
160555542005Essential role of BAX,BAK in B cell homeostasis and prevention of autoimmune disease.Takeuchi O et al
127719262003Genetic alterations in the coding region of the bak gene in uterine cervical carcinoma.Wani KM et al
109508692000tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.Wei MC et al
113260992001Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.Wei MC et al
159016722005Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins.Willis SN et al
172899992007Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak.Willis SN et al
169888402007Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis.Xu JX et al

Other Information

Locus ID:

NCBI: 578
MIM: 600516
HGNC: 949
Ensembl: ENSG00000030110


dbSNP: 578
ClinVar: 578
TCGA: ENSG00000030110


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
MicroRNAs in cancerKEGGhsa05206
MicroRNAs in cancerKEGGko05206
Programmed Cell DeathREACTOMER-HSA-5357801
Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
Activation and oligomerization of BAK proteinREACTOMER-HSA-111452
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
150771162004Mitochondrial p53 activates Bak and causes disruption of a Bak-Mcl1 complex.232
180566402007An androgen-regulated miRNA suppresses Bak1 expression and induces androgen-independent growth of prostate cancer cells.184
204603782010MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression.173
184719822008To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions.139
241626602014Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis.95
170154722006Inhibiting the mitochondrial fission machinery does not prevent Bax/Bak-dependent apoptosis.90
240749542013BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response.90
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
210413092011BH3 domains other than Bim and Bid can directly activate Bax/Bak.76
172278352007The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak.75


Grant Dewson ; Ruth Kluck

BAK1 (BCL2-antagonist/killer 1)

Atlas Genet Cytogenet Oncol Haematol. 2010-02-01

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