Regulation of TP53 Activity through Acetylation (Homo sapiens)

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1-3, 6-9, 17...542715144, 13, 1612, 16, 1877, 1154, 13, 152, 9, 19nucleoplasmcytosollate endosome lumenPIP4K2B KAT6A KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53 TetramerEP300KAT6A BRPF1 p-T369-KAT6A PML KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,p-S15,S20-TP53, BRD7:p-S15,S20-TP53:EP300EP300 PML ING5 BRD7p-S326-PIP4K2B p-S15,S20-TP53 PIP4K2A BRD1 CHD4 Ac-K120,p-S15,S20-TP53 ING2:EP300:Ac-K382,p-S15,S20-TP53 TetramerTMEM55Bp-T309,S474-AKT2 KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:p-S15,S20-TP53PIP4K2A BRPF1 ADPBRPF3 EP300 ING5 BRPF3 p-T, p-S-AKTPIP4K2C PIP4K2B BRD7:p-S15,S20-TP53:EP300RBBP7 Ac-K382,p-S15,S20-TP53 CHD3 p-S207,T211-MAP2K6ING5 KAT6A BRD1 MEAF6 PIP4K2C BRPF1 MEAF6 BRPF1 p-S15,S20-TP53 BRD1 p-S15,S20-TP53TetramerHDAC2 BRPF3 BRPF3 Ac-K120,K382,p-S15,S20-TP53 PIP4K2 dimersCoA-SHKAT6A Ac-K382,p-S15,S20-TP53 p-T305,S472-AKT3 PIP4K2A MTA2-NuRD complexp-T369-KAT6A:ING5:MEAF6:BRPF1,(2,3)PiING2 Ac-K120,K382,p-S15,S20-TP53 MEAF6 PIP4K2C ING2 BRD7 ADPBRPF3 EP300 MEAF6 acetatep-S326-PIP4K2BdimersAc-K382,p-S15,S20-TP53 p-T308,S473-AKT1 BRD1 ATPBRD7 ING2 p-S15,S20-TP53 p-S326-PIP4K2Bdimers:PIN1PI5PEP300 PIP4K2A MEAF6 ING2:EP300:p-S15,S20-TP53 TetramerBRPF3 MTA2 ING2:PI5PBRD1 PI(4,5)P2PMLGATAD2A MBD3 PIN1PIP4K2C ING5 RBBP4 ADPPIN1 BRPF1 BRD7:Ac-K382,p-S15,S20-TP53:EP300EP300 H2OGATAD2B BRD7 H2OPIP4K2B dimersBRPF1 PML Ac-CoAING5 p-S15,S20-TP53 BRD7:Ac-K382,p-S15,S20-TP53:EP300, KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53MEAF6 KAT6A KAT6A:ING5:MEAF6:BRPF1,(2,3)p-S326-PIP4K2B ING5 ATPING2PI5P ATPBRD7 BRD1 PML p-S15,S20-TP53 EP300 HDAC1 TMEM55B134, 13, 1552, 192, 19771010155, 1014, 20


Transcriptional activity of TP53 is positively regulated by acetylation of several of its lysine residues. BRD7 binds TP53 and promotes acetylation of TP53 lysine residue K382 by acetyltransferase EP300 (p300). Acetylation of K382 enhances TP53 binding to target promoters, including CDKN1A (p21), MDM2, SERPINE1, TIGAR, TNFRSF10C and NDRG1 (Bensaad et al. 2010, Burrows et al. 2010. Drost et al. 2010). The histone acetyltransferase KAT6A, in the presence of PML, also acetylates TP53 at K382, and, in addition, acetylates K120 of TP53. KAT6A-mediated acetylation increases transcriptional activation of CDKN1A by TP53 (Rokudai et al. 2013). Acetylation of K382 can be reversed by the action of the NuRD complex, containing the TP53-binding MTA2 subunit, resulting in inhibition of TP53 transcriptional activity (Luo et al. 2000). Acetylation of lysine K120 in the DNA binding domain of TP53 by the MYST family acetyltransferases KAT8 (hMOF) and KAT5 (TIP60) can modulate the decision between cell cycle arrest and apoptosis (Sykes et al. 2006, Tang et al. 2006). Studies with acetylation-defective knock-in mutant mice indicate that lysine acetylation in the p53 DNA binding domain acts in part by uncoupling transactivation and transrepression of gene targets, while retaining ability to modulate energy metabolism and production of reactive oxygen species (ROS) and influencing ferroptosis (Li et al. 2012, Jiang et al. 2015). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 6804758
Reactome version: 66
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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  1. Luo J, Su F, Chen D, Shiloh A, Gu W.; ''Deacetylation of p53 modulates its effect on cell growth and apoptosis.''; PubMed
  2. Drost J, Mantovani F, Tocco F, Elkon R, Comel A, Holstege H, Kerkhoven R, Jonkers J, Voorhoeve PM, Agami R, Del Sal G.; ''BRD7 is a candidate tumour suppressor gene required for p53 function.''; PubMed
  3. Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, Baer R, Gu W.; ''Ferroptosis as a p53-mediated activity during tumour suppression.''; PubMed
  4. Zou J, Marjanovic J, Kisseleva MV, Wilson M, Majerus PW.; ''Type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase regulates stress-induced apoptosis.''; PubMed
  5. Keune WJ, Jones DR, Bultsma Y, Sommer L, Zhou XZ, Lu KP, Divecha N.; ''Regulation of phosphatidylinositol-5-phosphate signaling by Pin1 determines sensitivity to oxidative stress.''; PubMed
  6. Tang Y, Luo J, Zhang W, Gu W.; ''Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.''; PubMed
  7. Rokudai S, Laptenko O, Arnal SM, Taya Y, Kitabayashi I, Prives C.; ''MOZ increases p53 acetylation and premature senescence through its complex formation with PML.''; PubMed
  8. Sykes SM, Mellert HS, Holbert MA, Li K, Marmorstein R, Lane WS, McMahon SB.; ''Acetylation of the p53 DNA-binding domain regulates apoptosis induction.''; PubMed
  9. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, Gottlieb E, Vousden KH.; ''TIGAR, a p53-inducible regulator of glycolysis and apoptosis.''; PubMed
  10. Clarke JH, Irvine RF.; ''Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization.''; PubMed
  11. Ullah M, Pelletier N, Xiao L, Zhao SP, Wang K, Degerny C, Tahmasebi S, Cayrou C, Doyon Y, Goh SL, Champagne N, Côté J, Yang XJ.; ''Molecular architecture of quartet MOZ/MORF histone acetyltransferase complexes.''; PubMed
  12. Bultsma Y, Keune WJ, Divecha N.; ''PIP4Kbeta interacts with and modulates nuclear localization of the high-activity PtdIns5P-4-kinase isoform PIP4Kalpha.''; PubMed
  13. Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J.; ''The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.''; PubMed
  14. Zhang Y, LeRoy G, Seelig HP, Lane WS, Reinberg D.; ''The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities.''; PubMed
  15. Pedeux R, Sengupta S, Shen JC, Demidov ON, Saito S, Onogi H, Kumamoto K, Wincovitch S, Garfield SH, McMenamin M, Nagashima M, Grossman SR, Appella E, Harris CC.; ''ING2 regulates the onset of replicative senescence by induction of p300-dependent p53 acetylation.''; PubMed
  16. Jones DR, Bultsma Y, Keune WJ, Halstead JR, Elouarrat D, Mohammed S, Heck AJ, D'Santos CS, Divecha N.; ''Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta.''; PubMed
  17. Li T, Kon N, Jiang L, Tan M, Ludwig T, Zhao Y, Baer R, Gu W.; ''Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence.''; PubMed
  18. Ciruela A, Hinchliffe KA, Divecha N, Irvine RF.; ''Nuclear targeting of the beta isoform of type II phosphatidylinositol phosphate kinase (phosphatidylinositol 5-phosphate 4-kinase) by its alpha-helix 7.''; PubMed
  19. Burrows AE, Smogorzewska A, Elledge SJ.; ''Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence.''; PubMed
  20. Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A, Reinberg D.; ''Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation.''; PubMed


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101388view11:27, 1 November 2018ReactomeTeamreactome version 66
100926view21:03, 31 October 2018ReactomeTeamreactome version 65
100465view19:37, 31 October 2018ReactomeTeamreactome version 64
100011view16:21, 31 October 2018ReactomeTeamreactome version 63
99564view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93888view13:43, 16 August 2017ReactomeTeamreactome version 61
93458view11:24, 9 August 2017ReactomeTeamreactome version 61
88145view13:01, 26 July 2016RyanmillerOntology Term : 'transcription pathway' added !
88144view12:59, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86553view09:20, 11 July 2016ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Ac-K120,K382,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
Ac-K120,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
Ac-K382,p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
BRD1 ProteinO95696 (Uniprot-TrEMBL)
BRD7 ProteinQ9NPI1 (Uniprot-TrEMBL)
BRD7:Ac-K382,p-S15,S20-TP53:EP300, KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53ComplexR-HSA-6805651 (Reactome)
BRD7:Ac-K382,p-S15,S20-TP53:EP300ComplexR-HSA-5628870 (Reactome)
BRD7:p-S15,S20-TP53:EP300ComplexR-HSA-3222096 (Reactome)
BRD7ProteinQ9NPI1 (Uniprot-TrEMBL)
BRPF1 ProteinP55201 (Uniprot-TrEMBL)
BRPF3 ProteinQ9ULD4 (Uniprot-TrEMBL)
CHD3 ProteinQ12873 (Uniprot-TrEMBL)
CHD4 ProteinQ14839 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
GATAD2A ProteinQ86YP4 (Uniprot-TrEMBL)
GATAD2B ProteinQ8WXI9 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
ING2 ProteinQ9H160 (Uniprot-TrEMBL)
ING2:EP300:Ac-K382,p-S15,S20-TP53 TetramerComplexR-HSA-6811488 (Reactome)
ING2:EP300:p-S15,S20-TP53 TetramerComplexR-HSA-3215194 (Reactome)
ING2:PI5PComplexR-HSA-6810382 (Reactome)
ING2ProteinQ9H160 (Uniprot-TrEMBL)
ING5 ProteinQ8WYH8 (Uniprot-TrEMBL)
KAT6A ProteinQ92794 (Uniprot-TrEMBL)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53 TetramerComplexR-HSA-6805637 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,p-S15,S20-TP53, BRD7:p-S15,S20-TP53:EP300ComplexR-HSA-6805649 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:p-S15,S20-TP53ComplexR-HSA-6805621 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3)ComplexR-HSA-6805616 (Reactome)
MBD3 ProteinO95983 (Uniprot-TrEMBL)
MEAF6 ProteinQ9HAF1 (Uniprot-TrEMBL)
MTA2 ProteinO94776 (Uniprot-TrEMBL)
MTA2-NuRD complexComplexR-HSA-6805654 (Reactome)
PI(4,5)P2MetaboliteCHEBI:18348 (ChEBI)
PI5P MetaboliteCHEBI:16500 (ChEBI)
PI5PMetaboliteCHEBI:16500 (ChEBI)
PIN1 ProteinQ13526 (Uniprot-TrEMBL)
PIN1ProteinQ13526 (Uniprot-TrEMBL)
PIP4K2 dimersComplexR-HSA-6811466 (Reactome)
PIP4K2A ProteinP48426 (Uniprot-TrEMBL)
PIP4K2B ProteinP78356 (Uniprot-TrEMBL)
PIP4K2B dimersComplexR-HSA-8877683 (Reactome)
PIP4K2C ProteinQ8TBX8 (Uniprot-TrEMBL)
PML ProteinP29590 (Uniprot-TrEMBL)
PMLProteinP29590 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RBBP4 ProteinQ09028 (Uniprot-TrEMBL)
RBBP7 ProteinQ16576 (Uniprot-TrEMBL)
TMEM55BProteinQ86T03 (Uniprot-TrEMBL)
acetateMetaboliteCHEBI:30089 (ChEBI)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S207,T211-MAP2K6ProteinP52564 (Uniprot-TrEMBL)
p-S326-PIP4K2B dimers:PIN1ComplexR-HSA-8877690 (Reactome)
p-S326-PIP4K2B dimersComplexR-HSA-8877680 (Reactome)
p-S326-PIP4K2B ProteinP78356 (Uniprot-TrEMBL)
p-T, p-S-AKTComplexR-HSA-202072 (Reactome)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-T369-KAT6A ProteinQ92794 (Uniprot-TrEMBL)
p-T369-KAT6A:ING5:MEAF6:BRPF1,(2,3)ComplexR-HSA-6805636 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-6805640 (Reactome)
ADPArrowR-HSA-6811522 (Reactome)
ADPArrowR-HSA-8877691 (Reactome)
ATPR-HSA-6805640 (Reactome)
ATPR-HSA-6811522 (Reactome)
ATPR-HSA-8877691 (Reactome)
Ac-CoAR-HSA-5628871 (Reactome)
Ac-CoAR-HSA-6805638 (Reactome)
Ac-CoAR-HSA-6811508 (Reactome)
BRD7:Ac-K382,p-S15,S20-TP53:EP300, KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53R-HSA-6805650 (Reactome)
BRD7:Ac-K382,p-S15,S20-TP53:EP300ArrowR-HSA-5628871 (Reactome)
BRD7:p-S15,S20-TP53:EP300ArrowR-HSA-3222093 (Reactome)
BRD7:p-S15,S20-TP53:EP300R-HSA-5628871 (Reactome)
BRD7:p-S15,S20-TP53:EP300mim-catalysisR-HSA-5628871 (Reactome)
BRD7R-HSA-3222093 (Reactome)
CoA-SHArrowR-HSA-5628871 (Reactome)
CoA-SHArrowR-HSA-6805638 (Reactome)
CoA-SHArrowR-HSA-6811508 (Reactome)
EP300R-HSA-3222093 (Reactome)
EP300R-HSA-6811479 (Reactome)
H2OR-HSA-6805650 (Reactome)
H2OR-HSA-6810410 (Reactome)
ING2:EP300:Ac-K382,p-S15,S20-TP53 TetramerArrowR-HSA-6811508 (Reactome)
ING2:EP300:p-S15,S20-TP53 TetramerArrowR-HSA-6811479 (Reactome)
ING2:EP300:p-S15,S20-TP53 TetramerR-HSA-6811508 (Reactome)
ING2:EP300:p-S15,S20-TP53 Tetramermim-catalysisR-HSA-6811508 (Reactome)
ING2:PI5PArrowR-HSA-6810376 (Reactome)
ING2R-HSA-6810376 (Reactome)
ING2R-HSA-6811479 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,K382,p-S15,S20-TP53 TetramerArrowR-HSA-6805638 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:Ac-K120,p-S15,S20-TP53, BRD7:p-S15,S20-TP53:EP300ArrowR-HSA-6805650 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:p-S15,S20-TP53ArrowR-HSA-6805620 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:p-S15,S20-TP53R-HSA-6805638 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3):PML:p-S15,S20-TP53mim-catalysisR-HSA-6805638 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3)R-HSA-6805620 (Reactome)
KAT6A:ING5:MEAF6:BRPF1,(2,3)R-HSA-6805640 (Reactome)
MTA2-NuRD complexmim-catalysisR-HSA-6805650 (Reactome)
PI(4,5)P2ArrowR-HSA-6811522 (Reactome)
PI(4,5)P2R-HSA-6810410 (Reactome)
PI5PArrowR-HSA-6810410 (Reactome)
PI5PArrowR-HSA-6811508 (Reactome)
PI5PR-HSA-6810376 (Reactome)
PI5PR-HSA-6811522 (Reactome)
PIN1R-HSA-8877692 (Reactome)
PIP4K2 dimersmim-catalysisR-HSA-6811522 (Reactome)
PIP4K2B dimersR-HSA-8877691 (Reactome)
PMLR-HSA-6805620 (Reactome)
PiArrowR-HSA-6810410 (Reactome)
R-HSA-3222093 (Reactome) The N-terminal region of BRD7, upstream of its bromodomain that is responsible for interaction with chromatin, binds the C-terminus of TP53 (p53) (Drost et al. 2010, Burrows et al. 2010). BRD7 also binds and can recruit EP300 (p300) to TP53 target promoters CDKN1A and MDM2 (Drost et al. 2010). BRD7 positively regulates transcription of other TP53 targets: SERPINE1, TIGAR (Bensaad et al. 2006), TNFRSF10C and NDGR1, presumably via a similar mechanism as in the case of CDKN1A and MDM2 (Drost et al. 2010, Burrows et al. 2010).
R-HSA-5628871 (Reactome) BRD7 promotes EP300 (p300)-mediated acetylation of TP53 on lysine residue K382, which enhances binding of TP53 to its target promoters. Also, BRD7 induces EP300-mediated acetylation of histone 3 on lysine residue K10 (also labeled in literature as K9), creating the H3K9 active chromatin mark at CDKN1A and MDM2 promoters (Drost et al. 2010), and possibly other TP53 promoters co-regulated by BRD7, such as SERPINE1, TIGAR, TNFRSF10C and NDRG1.
R-HSA-6805620 (Reactome) The histone acetyltransferase KAT6A, which functions as part of the MOZ/MORF complex (Ullah et al. 2008), associates with TP53 (p53) and PML (Rokudai et al. 2013). KAT6A can independently associate with TP53 and PML, but the presence of PML enhances KAT6A-mediated acetylation of TP53. Phosphorylation of KAT6A by activated AKT inhibits PML binding (Rokudai et al. 2013).
R-HSA-6805638 (Reactome) KAT6A histone acetyltransferase, part of the MOZ/MORF complex, acetylates TP53 (p53) on lysine residues K120 and K382. The acetylation of TP53 by KAT6A is enhanced in the presence of PML and results in increased transcriptional activation of the CDKN1A (p21) gene by TP53 (Rokudai et al. 2013).
R-HSA-6805640 (Reactome) Activated AKT phosphorylates the histone acetyltransferase KAT6A on threonine residue T369, preventing association of PML with the KAT6A complex and repressing KAT6A-mediated acetylation of TP53 (p53) (Rokudai et al. 2013).
R-HSA-6805650 (Reactome) MTA2 (PID), a component of the NuRD complex, binds TP53 (p53) and thus targets histone deacetylases of the NuRD complex to TP53. The NuRD complex deacetylates the C-terminus of TP53, including acetylated lysine K382, thus inhibiting TP53 transcriptional activity (Luo et al. 2000).
R-HSA-6810376 (Reactome) The PHD finger of ING2 binds phosphatidylinositol-5-phosphate (PI5P) (Gozani et al. 2003), which promotes nuclear retention of ING2 (Jones et al. 2006, Zou et al. 2007).
R-HSA-6810392 (Reactome) Under conditions of cellular stress, TMEM55B (type I phosphatidylinositol 4,5-bisphosphate 4-phosphatase) translocates to the nucleus through an unknown mechanism (Zou et al. 2007).
R-HSA-6810410 (Reactome) Translocation of TMEM55B (type I phosphatidylinositol 4,5-bisphosphate 4-phosphatase) to the nucleus under conditions of cellular stress leads to dephosphorylation of nuclear PI(4,5)P2 to PI5P, thus increasing the concentration of PI5P in the nucleus (Zou et al. 2007). PIP2 and its derivatives are not associated with nuclear envelope structures (Bornenkov et al. 1998) but localize to poorly defined subnuclear compartments called nuclear specks (reviewed by Barlow et al. 2010).
R-HSA-6811479 (Reactome) ING2 recruits histone acetyltransferase EP300 (p300) to TP53 (Padeux et al. 2005).
R-HSA-6811508 (Reactome) The histone acetyltransferase EP300 (p300), recruited to TP53 (p53) by ING2, acetylates TP53 on lysine residue K382, which may contribute to TP53-dependent apoptosis (Padeux et al. 2005). PI5P positively regulates TP53 acetylation (Zou et al. 2007), possibly by increasing the amount of ING2 in the nucleus (Gozani et al. 2003).
R-HSA-6811522 (Reactome) In the nucleus, phosphatidylinositol 5-phosphate (PI5P) is phosphorylated to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) mainly by phosphatidylinositol-5-phosphate 4-kinase type-2 beta (PIP4K2B). In the nucleus, PIP4K2B predominantly functions as a homodimer or a heterodimer with PIP4K2A. A low level of PIP4K2A homodimers can also be found in the nucleus. Nuclear localization of PIP4K2C has not been examined but is assumed to be possible, at least through formation of heterodimers with PIP4K2B (Ciruela et al. 2000, Jones et al. 2006, Bultsma et al. 2010). Under conditions of cellular stress, nuclear PIP4K2B can be phosphorylated by p38 MAP kinases, resulting in PIP4K2B inactivation. The putative p38 target site, serine residue S326 of PIP4K2B, is conserved in PIP4K2A, but the role and mechanism of p38-mediated regulation of PIP4K2 isoforms has not been studied in detail (Jones et al. 2006).
R-HSA-8877691 (Reactome) Under conditions of cellular stress, such as increased level of reactive oxygen species, MAP2K6 (MKK6), and possibly other kinases of the p38 MAPK family, phosphorylates PIP4K2B at serine residue S326. Threonine residue T322 of PIP4K2B is also phosphorylated under stress conditions, but the responsible kinase is not known. MAP2K6 may also phosphorylate PIP4K2A, but not PIP4K2C (Kuene et al. 2012).
R-HSA-8877692 (Reactome) Peptidyl-prolyl cis-trans isomerase PIN1 binds to PIP4K2B phosphorylated at serine residue S326. PIP4K2B is phosphorylated at S326 under conditions of cellular stress, such as increased level of reactive oxygen species (ROS). Phosphorylation of PIP4K2B at threonine residue T322 may also contribute to PIN1 binding. PIN1 induces conformational change of PIP4K2B, resulting in inactivation of PIP4K2B dimers. This enables increase of the nuclear PI5P levels. PI5P positively regulates expression of genes involved in neutralization of ROS (Keune et al. 2012).
TMEM55BArrowR-HSA-6810392 (Reactome)
TMEM55BR-HSA-6810392 (Reactome)
TMEM55Bmim-catalysisR-HSA-6810410 (Reactome)
acetateArrowR-HSA-6805650 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-3222093 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6805620 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-6811479 (Reactome)
p-S207,T211-MAP2K6mim-catalysisR-HSA-8877691 (Reactome)
p-S326-PIP4K2B dimers:PIN1ArrowR-HSA-8877692 (Reactome)
p-S326-PIP4K2B dimersArrowR-HSA-8877691 (Reactome)
p-S326-PIP4K2B dimersR-HSA-8877692 (Reactome)
p-T, p-S-AKTTBarR-HSA-6805620 (Reactome)
p-T, p-S-AKTmim-catalysisR-HSA-6805640 (Reactome)
p-T369-KAT6A:ING5:MEAF6:BRPF1,(2,3)ArrowR-HSA-6805640 (Reactome)
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