BAD

Protein BAD map

Identifiers
BCL2-associated agonist of cell death
HUGO:BAD HGNC:936 ENTREZ:572 UNIPROT:Q92934 GENECARDS:BAD REACTOME:50663 KEGG:572 ATLASONC:BADID130ch11q13 WIKI:BAD

Maps_Modules
 EMT  map  / EMT_REGULATORS  map
 Apoptosis  map  / APOPTOSIS_GENES  map
 Apoptosis  map  / MITOCH_METABOLISM  map
 Apoptosis  map  / MOMP_REGULATION  map
 Survival  map  / MAPK  map
 Survival  map  / PI3K_AKT_MTOR  map
 Survival  map  / WNT_NON_CANONICAL  map

References
PMID:22039431
The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates.
The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family.
Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic proteins) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic proteins) work against programmed cell death.
The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function.
Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis
PMID:12175651
PMID:10826997
PMID:12767520
PMID:19030972
PMID:16931767
PMID:21540285
PMID:12444011
IGFfamily exhibits anti-apoptotic activity.
Three IGF1R-induced anti-apoptotic pathways:
1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation.
Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death.
Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death.
2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD.
3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5)
IRS3 and IRS4 however have negative effect on anti-apoptotic effects of IGFR.
there are at least 2 isoforms of BAD. Here, protein BAD refers to any of the different isoforms. Numbering of amino-acids, used for phosphorylation sites, are adjusted to the ‘canonical’ isoform as defined in Uniprot. This lead to choosing different isoforms for different organisms.
A mitochondrial pool of Raf-1 (C-RAF) molecules which do not activate MEK reportedly exert their prosurvival effects upstream of cytochrome c release by phosphorylating the pro-apoptotic Bcl-2 family member BAD. Phosphorylation of BAD results in its translocation to the cytosol and ultimately in the inhibition of cytochrome c release.
PMID:12107820
PMID:10949026
PMID:19641503

BAD@Mitochondria

References
e_re1610( EMT  map ):
PMID:12175651
PMID:10826997
PMID:12767520
PMID:19030972
PMID:16931767
PMID:21540285
PMID:12444011
IGFfamily exhibits anti-apoptotic activity.
Three IGF1R-induced anti-apoptotic pathways:
1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation.
Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death.
Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death.
2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD.
3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5)

BAD|​pho@Mitochondria

References
e_re1610( EMT  map ):
PMID:12175651
PMID:10826997
PMID:12767520
PMID:19030972
PMID:16931767
PMID:21540285
PMID:12444011
IGFfamily exhibits anti-apoptotic activity.
Three IGF1R-induced anti-apoptotic pathways:
1. IRS1-mediated pathway causing activation of PI3K and AKT(PKB) leading to BAD phosphorylation.
Unphosphorylated BAD, by binding to BCLXL and BCL2, neutralizes the protective effect of these 2 later proteins and promotes cell death.
Phosphorylated BAD is sequestered by 14-3-3 protein family and thus unable to bind BCL2 family hence can not promote cell death.
2. After autophosphorylation and thus activation, IGF1R binds to 14-3-3 protein family, leading to activation and translocation of c-Raf1 to the mitochondria where it phosphorylates BAD.
3. IGF1R specifically phosphorylates and inhibits ASK1 (MAP3K5)

BAD|​pho@Cytoplasm

References
a_re631( Apoptosis  map ):
logical:re631_s3146_re638=FALSE
PMID:9381178
in FL5.12 (murine pro-B-cell lymphoid cell, IL-3 dependent) BAD phosphorylated upon IL-3
in 293T, over-expression of wt Akt or myr-Akt, but not kinase mutant induces phosphorylation of BAD
in vitro phosphorylation of BAD by Akt, BAD S112(human S75)A-S136(human S99)A not phosphorylated
PMID:8929531
2D tryptic peptide mapping identifies S112(human S75) and S136(human S99) as the phospho-sites
phsophorylation in FL5.12 in response to IL-3 or PMA
PMID:9346240
in vitro, purified Akt phosphorylates recombinant BAD at S136(human S99) but not at S112(human S75) (serine mutants)
in Balb/c 3T3 upon PDGF or PC12 upon NGF, BAD phosphorylated in an Akt-dependent manner (wortmannin, LY294002)
partial evidence for BAD:Akt interaction
PMID:10230394
mitochondria localized PKA is a BAD-S112(human S75) kinase
PMID:10558990
in vitro purified activated RSK2/RPS6KA3 phosphorylates a peptide encompassing BAD S112(humanS75) phospho-site. Far less efficient as a BAD-S136 kinase
in 293T, over-expression of RSK2 and MEK1 induces phsophorylation of BAD (anti-BAD pS112)
in BDNF-treated cerebellar granule cells, BDNF induces S112 phosphorylation of BAD, in a MEK1-dependent manner (PD098059)
PMID:10837486
RSK is a BAD S112 kinase (anti BAD-phosphoS112)
in vitro,
in HEK293 upon forskolin TPA isoproterenol or insulin-like growth factor, PKA mediated phosphorylation of S155 of murine BAD (human S118)
S118 lies in the BH3 domain of BAD
phosphorylation of S155 independent of that of S112/136
RSK1-2-3 are BAD S155 kinases
PMID:12954615
in vitro, murine PIM2 immunoprecipitated from trasfected U2OS phosphorylates BAD
in U2OS, PIM2 expression but not that of a kinase dead mutant induces BAD S112 phosphorylation
in FDCP1 murine IL3 dependent hematopoietic cells, upon IL3 withdrawal or doxorubicin, PIM2 ectopic expression is protective
PMID:15280015
BAD S112 phosphorylation by PIM1
PMID:17270021
in SW480 human colon carcinoma cell line, correlation between PIM3 expression and BAD phosphorylation. siRNA against PIM3 abrogates BAD S112 and S136 phosphorylation and induces apoptosis
in a set of human colon cancers, correlation and colocalization of PIM3 and BAD phospho-S112
PMID:11493700
S6K purified as a BAD kinase from FL5.12 BCL-XL/BAD cells
in vitro with recombinant proteins, BAD S136 phosphorylation
in FL5.12 by S6K upon IGF, inhibited by rapamycin
in ES p70S6K-/- cells, IGF-induced BAD S136 phosphorylation is lost
PMID:10611223
in FL5.12 upon IL3, PAK1 phosphorylates BAD on S112 and S136, which results in decreased interaction with BCL2 and BCL2L1, and increased interaction with 14-3-3
a_re1420( Apoptosis  map ):
PMID:8929532
in vitro RAF1:BCL2 interaction
in 293, overexpression of BCL2 induces relocalization of RAF1-GFP to mitochondria
in vitro phosphorylation of BAD by RAF1
in 293T, over-expression of a mitochondria-targeted version of RAF1 induces phosphorylation of BAD (controls: plasma membrane targeted RAF1, kinase dead mutant)
BCL2 over-expression targets RAF1 kinase domain-GFP to mitochondria
mitochondria-targeted RAF1 (deleted for Ras binding domain) potentiates BCL2 anti-apoptotic activity in 32D.3 exposed to staurosporine or upon IL-3 withdrawal
a_re632( Apoptosis  map ):
logical:re632_s2093=FALSE
interaction between BAD S155 and 14-3-3 delta and epsilon
in FL5.12 co-IP of mouse BAD phosphorylated and YWHAQ
in FL5.12 BAD phosphorylated only on S112 or S136 still binds 14-3-3 (S to A mutants, co-IP)
in FL5.12 phosphorylation and binding to 14-3-3 inhibits BAD interaction with Bcl-XL and pro-apoptotic activity
PMID:12657644
in 293T, BAD:YWHAE interaction, inhibited by caspase-mediated cleavage of YWHAE
PMID:17979178
BAD:YWHAH interaction tandem affinity purification in a complex with Raf (cited by IntAct)
a_re633( Apoptosis  map ):
logical:re633_s3146_re638=FALSE
PMID:10195903
in 293T cells or 293T cells expressing constitutively active Akt, upon over-expression of constitutive active calcineurin (DeltaCnA/CnB)
in HCT116 colon cancer cells, Ca2+ increase (thapsigargin, ionomycin) inhibits BAD S75 phosphorylation and interaction of BAD with 14-3-3 or PP3CB.
in transfected 293T, co-IP BAD phosphomimetic mutant with PPP3CB
in Du145 prostate cancer cells, Ca2+ induced dephosphorylation of BAD correlates with its relocalization to mitochondria
in CSM14.1 immortalized rat hippocampal cells, exogenously expressed BAD-GFP relocalizes to mitochondria in response to cytoplasmic Ca2+ increased (THG, A23187)
in primaryin primary rat hippocampal neurons, L-glutamate induces cell death and relocalization to mitochondria of BAD-GFP, which are both inhibited by co-expression of dominant negative DeltaCnA(H101Q)
in 293T cells or 293T cells expressing mitochondria-targeted RAF1, upon over-expression of constitutive active calcineurin (DeltaCnA/CnB)
a_re638( Apoptosis  map ):
reactionType:is.a

BAD|​unk@Cytoplasm

References
a_re638( Apoptosis  map ):
reactionType:is.a
logical:re631_s3146_re638=FALSE
logical:re633_s3146_re638=FALSE
a_re630( Apoptosis  map ):
PMID:12049737
in vitro with recombinant murine proteines
in COS cells with ectopic expression of BAD
in rat granule neurons upon suppression of neuronal activity, cdc2 is induced, phosphorylates BAD S128
in rat neurones expressing ectopic proteins, cdc2 induced apoptosis is inhibited by a BAD S118 mutant
in vitro, AKT mediated BAD S136 phosphorylation is not blocked by prior cdc2 mediated BAD S128 phosphorylations
BAD S128 phosphorylation inhibits BAD phospho S136 : 14-3-3 interaction
a_re1242( Apoptosis  map ):
PMID:11287608
in 32D murine cells, upon IL3 withdrawal, BAD cleavage
in vitro cleavage of BAD by recombinant CASP 2,3,7,8,10, and GZMB

BAD|​S91_unk|​active@Cytoplasm

References
a_re1244:( Apoptosis  map ) reactionType:is.a
a_re597:( Apoptosis  map ) testtest
a_re641( Apoptosis  map ):
PMID:12931191
in mouse liver mitochondria, protein complex purification

BAD|​S91_pho|​unk@Cytoplasm

References
a_re630( Apoptosis  map ):
PMID:12049737
in vitro with recombinant murine proteines
in COS cells with ectopic expression of BAD
in rat granule neurons upon suppression of neuronal activity, cdc2 is induced, phosphorylates BAD S128
in rat neurones expressing ectopic proteins, cdc2 induced apoptosis is inhibited by a BAD S118 mutant
in vitro, AKT mediated BAD S136 phosphorylation is not blocked by prior cdc2 mediated BAD S128 phosphorylations
BAD S128 phosphorylation inhibits BAD phospho S136 : 14-3-3 interaction
a_re1244:( Apoptosis  map ) reactionType:is.a

BAD@Cytoplasm

References
a_re633( Apoptosis  map ):
logical:re633_s3146_re638=FALSE
PMID:10195903
in 293T cells or 293T cells expressing constitutively active Akt, upon over-expression of constitutive active calcineurin (DeltaCnA/CnB)
in HCT116 colon cancer cells, Ca2+ increase (thapsigargin, ionomycin) inhibits BAD S75 phosphorylation and interaction of BAD with 14-3-3 or PP3CB.
in transfected 293T, co-IP BAD phosphomimetic mutant with PPP3CB
in Du145 prostate cancer cells, Ca2+ induced dephosphorylation of BAD correlates with its relocalization to mitochondria
in CSM14.1 immortalized rat hippocampal cells, exogenously expressed BAD-GFP relocalizes to mitochondria in response to cytoplasmic Ca2+ increased (THG, A23187)
in primaryin primary rat hippocampal neurons, L-glutamate induces cell death and relocalization to mitochondria of BAD-GFP, which are both inhibited by co-expression of dominant negative DeltaCnA(H101Q)
in 293T cells or 293T cells expressing mitochondria-targeted RAF1, upon over-expression of constitutive active calcineurin (DeltaCnA/CnB)
a_re631( Apoptosis  map ):
logical:re631_s3146_re638=FALSE
PMID:9381178
in FL5.12 (murine pro-B-cell lymphoid cell, IL-3 dependent) BAD phosphorylated upon IL-3
in 293T, over-expression of wt Akt or myr-Akt, but not kinase mutant induces phosphorylation of BAD
in vitro phosphorylation of BAD by Akt, BAD S112(human S75)A-S136(human S99)A not phosphorylated
PMID:8929531
2D tryptic peptide mapping identifies S112(human S75) and S136(human S99) as the phospho-sites
phsophorylation in FL5.12 in response to IL-3 or PMA
PMID:9346240
in vitro, purified Akt phosphorylates recombinant BAD at S136(human S99) but not at S112(human S75) (serine mutants)
in Balb/c 3T3 upon PDGF or PC12 upon NGF, BAD phosphorylated in an Akt-dependent manner (wortmannin, LY294002)
partial evidence for BAD:Akt interaction
PMID:10230394
mitochondria localized PKA is a BAD-S112(human S75) kinase
PMID:10558990
in vitro purified activated RSK2/RPS6KA3 phosphorylates a peptide encompassing BAD S112(humanS75) phospho-site. Far less efficient as a BAD-S136 kinase
in 293T, over-expression of RSK2 and MEK1 induces phsophorylation of BAD (anti-BAD pS112)
in BDNF-treated cerebellar granule cells, BDNF induces S112 phosphorylation of BAD, in a MEK1-dependent manner (PD098059)
PMID:10837486
RSK is a BAD S112 kinase (anti BAD-phosphoS112)
in vitro,
in HEK293 upon forskolin TPA isoproterenol or insulin-like growth factor, PKA mediated phosphorylation of S155 of murine BAD (human S118)
S118 lies in the BH3 domain of BAD
phosphorylation of S155 independent of that of S112/136
RSK1-2-3 are BAD S155 kinases
PMID:12954615
in vitro, murine PIM2 immunoprecipitated from trasfected U2OS phosphorylates BAD
in U2OS, PIM2 expression but not that of a kinase dead mutant induces BAD S112 phosphorylation
in FDCP1 murine IL3 dependent hematopoietic cells, upon IL3 withdrawal or doxorubicin, PIM2 ectopic expression is protective
PMID:15280015
BAD S112 phosphorylation by PIM1
PMID:17270021
in SW480 human colon carcinoma cell line, correlation between PIM3 expression and BAD phosphorylation. siRNA against PIM3 abrogates BAD S112 and S136 phosphorylation and induces apoptosis
in a set of human colon cancers, correlation and colocalization of PIM3 and BAD phospho-S112
PMID:11493700
S6K purified as a BAD kinase from FL5.12 BCL-XL/BAD cells
in vitro with recombinant proteins, BAD S136 phosphorylation
in FL5.12 by S6K upon IGF, inhibited by rapamycin
in ES p70S6K-/- cells, IGF-induced BAD S136 phosphorylation is lost
PMID:10611223
in FL5.12 upon IL3, PAK1 phosphorylates BAD on S112 and S136, which results in decreased interaction with BCL2 and BCL2L1, and increased interaction with 14-3-3
a_re1243:( Apoptosis  map ) reactionType:is.a

BAD|​pho|​pho@Cytoplasm

References
s_wnc2_re30:( Survival  map ) PMID:22088220

BAD|​pho|​pho@Mitochondria

References
s_wnc2_re31:( Survival  map ) PMID:22088220


Modifications:
In compartment: Cytoplasm
  1. BAD@Cytoplasm map

  2. BAD|​pho@Cytoplasm map
  3. BAD|​unk@Cytoplasm map
  4. BAD|​pho|​pho@Cytoplasm map
  5. BAD|​S91_pho|​unk@Cytoplasm map
  6. BAD|​S91_unk|​active@Cytoplasm map

In compartment: Mitochondria

  1. BAD@Mitochondria map

  2. BAD|​pho@Mitochondria map
  3. BAD|​pho|​pho@Mitochondria map

Participates in complexes:
In compartment: Cytoplasm

  1. 14-3-3*:​BAD|​pho@Cytoplasm map

In compartment: Mitochondria

  1. BAD:​BAD_binding partners*@Mitochondria map

  2. 14-3-3*:​BAD|​S112_pho|​S136_pho@Mitochondria map
  3. 14-3-3*:​BAD|​pho|​pho|​pho@Mitochondria map
  4. 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map
  5. 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map

In compartment: Mitochondrial outer membrane

  1. BAD|​S91_unk:​BCL2@Mitochondrial outer membrane map

  2. BAD|​S91_unk:​BCL2L2@Mitochondrial outer membrane map
  3. BAD|​S91_unk:​BCL2-XL*@Mitochondrial outer membrane map
  4. BAD|​S91_unk:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map
  5. BAD|​S91_unk|​pho:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map

Participates in reactions:
As Reactant or Product:

  1. BAD|​unk@Cytoplasm map map cleaved~BAD*@Cytoplasm map

  2. BAD@Cytoplasm map map BAD|​unk@Cytoplasm map
  3. BAD|​S91_pho|​unk@Cytoplasm map map BAD|​S91_unk|​active@Cytoplasm map
  4. cleaved~BAD*@Cytoplasm map map BAD|​S91_unk|​active@Cytoplasm map
  5. BAD|​S91_unk:​BCL2@Mitochondrial outer membrane map map BCL2@Mitochondrial outer membrane map + BAD|​pho@Cytoplasm map
  6. BAD|​S91_unk|​active@Cytoplasm map + BCL2|​pho@Mitochondrial outer membrane map map BAD|​S91_unk:​BCL2@Mitochondrial outer membrane map
  7. BAD|​S91_unk|​active@Cytoplasm map + BCL2-XL*@Mitochondrial outer membrane map map BAD|​S91_unk:​BCL2-XL*@Mitochondrial outer membrane map
  8. BAD|​S91_unk|​active@Cytoplasm map + BCL2L2@Mitochondrial outer membrane map map BAD|​S91_unk:​BCL2L2@Mitochondrial outer membrane map
  9. BAD|​unk@Cytoplasm map map BAD|​S91_pho|​unk@Cytoplasm map
  10. BAD@Cytoplasm map map BAD|​pho@Cytoplasm map
  11. BAD|​pho@Cytoplasm map + 14-3-3*|​unk@Cytoplasm map map a_s3150
  12. BAD|​pho@Cytoplasm map map BAD@Cytoplasm map
  13. BAD|​pho@Cytoplasm map map BAD|​unk@Cytoplasm map
  14. BAD|​S91_unk|​active@Cytoplasm map + GCK@Cytoplasm map + WASF1@Cytoplasm map + PRKAC*@Cytoplasm map + PPP1C*@Cytoplasm map map BAD|​S91_unk:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map
  15. BAD|​S91_unk:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map map BAD|​S91_unk|​pho:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map
  16. BAD|​S91_unk|​pho:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map map BAD|​S91_unk:​GCK:​PPP1C*:​PRKAC*:​WASF1@Mitochondrial outer membrane map
  17. BAD@Mitochondria map map BAD|​pho@Mitochondria map
  18. BAD_binding partners*@Mitochondria map + BAD@Mitochondria map map BAD:​BAD_binding partners*@Mitochondria map
  19. BAD:​BAD_binding partners*@Mitochondria map map Apoptosis@Cytoplasm map
  20. BAD|​pho@Mitochondria map + 14-3-3*@Cytoplasm map map 14-3-3*:​BAD|​pho@Cytoplasm map
  21. s_s_akt1_s528 + 14-3-3*@Mitochondria map map 14-3-3*:​BAD|​S112_pho|​S136_pho@Mitochondria map
  22. 14-3-3*:​BAD|​S112_pho|​S136_pho@Mitochondria map map 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map
  23. 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map map 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map + BCL2-XL*@Mitochondria map
  24. 14-3-3*:​BAD|​S112_pho|​S136_pho|​S155_pho@Mitochondria map map s_s_akt1_s561
  25. BAD@Mitochondria map map BAD|​pho@Cytoplasm map
  26. BAD@Mitochondria map map Apoptosis@Cytoplasm map
  27. s_s_mpk1_s953 map BCL2@Mitochondria map + BAD@Mitochondria map
  28. 14-3-3*:​BAD|​pho|​pho|​pho@Mitochondria map map Survival@Mitochondria map
  29. BAD|​pho|​pho@Mitochondria map map MOMP@Mitochondria map
  30. 14-3-3*:​BAD|​pho|​pho|​pho@Mitochondria map map s_s_wnc2_s86
  31. s_s_wnc2_s77 map BAD|​pho|​pho@Cytoplasm map + 14-3-3*@Cytoplasm map
  32. BAD|​pho|​pho@Cytoplasm map map BAD|​pho|​pho@Mitochondria map
  33. PI3K Akt MTOR pathway@Cytoplasm map map 14-3-3*:​BAD|​pho|​pho|​pho@Mitochondria map

As Catalyser:

  1. glucose@Cytoplasm map + ATP@Cytoplasm map map glucose-6P@Cytoplasm map + ADP@Cytoplasm map

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