Factors involved in megakaryocyte development and platelet production (Homo sapiens)

From WikiPathways

Jump to: navigation, search
1, 36, 3732, 332124263431995102512, 231827, 391711, 30, 31, 35, 38161462254, 20729cytosolendosome lumenmitochondrial matrixnucleoplasmMeK-H3F3A AKAP1 CAPZA2 NFE2ITPK1GATA proteinsIRF1:Promotors ofIFN alpha, IFN betaHistone H3methylated atlysine-9DOCK8 IFNA21 gene RAC1 ADPDOCK-GEFsGlobin genesIRF2:promoters ofINF alpha, INF betaKDM1A EHD2 JMJD1CCABLES1 DOCK11 Histone H3 IFNA7 gene CABLES2 IFNA2 gene GATA1 GATA4 Histone H3 methylated at lysine-9 ZFPM1, ZFPM2IFNA10 gene IFNA4 gene ADPSH2Bfamily:p-Y813-JAK2IFNB1 gene GTPIRF2REST DNA binding sites IFNA17 gene p53:MYB:SIN3ANADPHCAPZB DOCK6 ATPZFPM2 AKAP10 CDK2DOCK10 PRKAR1A Promotor region ofbeta-globinI(3,4,5,6)P4IFNA8 gene CAPZA2 LRRC16APRKAR1B RAD51B:RAD51C:Single-stranded DNAI(1,3,4,5,6)P5I(1,3,4)P3MFN2 MYBHBD gene HBG2CAPZA1 MAFK CDK5BHC complexMAFK RCOR1 MeK-H3F3A DOCK7 CAPZA1 EHD1 EHD2 MFN2 Dual-specificAKAPs:PKA tetramerNADP+IFN alpha/beta(IFNA/B)MitofusinsSmall Maf familymembersIFNA CBX5MeK-HIST2H3A ZFPM proteins:GATAproteinsIFNA7 gene GATA5 DOCK9 CAPZB RAD51C IFNA4 gene CDC42 RAB5AGATA2 Promotor region of beta-globin IFNA2 gene RAC1, CDC42CAPZA1 HBG1 gene DOCK1 LRRC16A DOCK11 ABL1 DOCK8 SH2B3 IFNA6 gene HMG20B Histone H3 mono ordi-methylated at K9LRRC16A:F-actincapping proteinVPS45DOCK5 CDC42 PRKAR2A HDAC1 IFNA14 gene NF-E2:Promoterregion ofbeta-globinHBE1TP53 TetramerGATA1 IFNA7 gene RAD51C IFNA8 gene MICAL1:FADRAD51B:RAD51CMAFK IFNA10 gene PRKACG IFNB1 WEE1 EHD3 CABLES1 ZFPM1 adenosine5'-monophosphateCDK2:CABLES1:WEE1PHF21A NF-E2MAFG GATA3 IRF2 Histone H3 methylated at lysine-9 CBX5 MAFG DOCK2 ZFPM2 I(1,3,4,6)P4PKA tetramerp-Y813-JAK2 Mitofusin complexO2ABL1REST DNA binding sites CABLES1KDM1A PRKACA IFNA4 gene MAFF CAPZBGDPPRKAR2A CABLES2 IFNA17 gene ATPEHD3 RAC1 PRKAR2B IFNA21 gene SH2B1 REST:REST DNAbinding sitesI(1,3,4,5)P4DOCK7 ZFYVE20 F-actin cappingproteinRCOR1 MAFF DOCK1 DOCK5 PRKAR1B CAPZA2 HBDAK3DOCK2 PRKACB ADPDOCK6 p-Y813-JAK2ZFYVE20 Histone H3 dimethylated at lysine-9 CAPZA2 DOCK4 EHD1 CAPZB Rabenosyn-5:VPS-45TP53 DOCK9 MeK-HIST2H3A SH2B familyZFYVE20HDAC2 CDK5:CABLES:ABLPRKAR1A DOCK3 IFNA16 gene SH2B2 HP1alpha:Histone H3methylated at K9CDK5 IFNA21 gene KinesinsIFNA6 gene GATA4 RAD51B SH2B3 H2O2MFN1 C-terminal EH domaincontaining proteinsSingle-stranded DNAIFNA5 gene F-actin cappingprotein alphasubunitMeK10-HIST1H3A IFNA genesDOCK3 ZFPM1 PRKACB IFNA17 gene MICAL1 Histone H3 mono- orunmethylated at K9IFNA6 gene DOCK-GEFs:RAC1,CDC42GATA3 IFNB1 gene HBBIFNA14 gene SIN3A IRF1GATA6 GATA6 IFNB1 geneIFNA1 gene HDAC1 IFNA16 gene GATA5 CAPZA1 IFNA16 gene CABLES1 Dual-specific AKAPsCDK2 IRF1 RCOR1 BHCcomplex:REST:RESTDNA binding sitesPRKACA VPS45 PRKAR2B RAD51CNFE2 IFNA5 gene SH2B2 Type-I IFN genesHMG20B IFNB1 gene HDAC2 RAB5A DOCK4 HBG1IFNA10 gene AKAP1 F-actin cappingprotein:f-actinf-actinHBB gene MFN1 IFNA1 gene SH2B1 PRKACG HBE1 gene FAD C-terminalEHdomaincontainingproteins:Rabenosyn-5SIN3APHF21A CABLESMAFG RAD51BNFE2 DOCK10 MYB IFNA2 gene IFNA8 gene IFNA1 gene GATA2 f-actin Single-stranded DNA WEE1MeK10-HIST1H3A IFNA14 gene AKAP10 IFNA genes HBG2 gene RAD51B MAFF TP53 IFNA5 gene 2, 8, 15, 28713


Megakaryocytes (MKs) give rise to circulating platelets (thrombocytes) through terminal differentiation of MKs which release cytoplasmic fragments as circulating platelets. As MKs mature they undergo endoreduplication (polyploidisation) and expansion of cytoplasmic mass to cell sizes larger than 50-100 microns, and ploidy ranges up to 128 N. As MKs mature, the polyploid nucleus becomes horseshoe-shaped, the cytoplasm expands, and platelet organelles and the demarcation membrane system are amplified. Proplatelet projections form which give rise to de novo circulating platelets (Deutsch & Tomer 2006).
The processes of megakaryocytopoiesis and platelet production occur within a complex microenvironment where chemokines, cytokines and adhesive interactions play major roles (Avecilla et al. 2004). Megakaryocytopoiesis is regulated at several levels including proliferation, differentiation and platelet release (Kaushansky 2003). Thrombopoietin (TPO/c-Mpl ligand) is the most potent cytokine stimulating proliferation and maturation of MK progenitors (Kaushansky 2005) but many other growth factors are involved. MK development is controlled by the action of multiple transcription factors. Many MK-specific genes are co-regulated by GATA and friend of GATA (FOG), RUNX1 and ETS proteins. Nuclear factor erythroid 2 (NF-E2), which has an MK-erythroid specific 45-kDa subunit, controls terminal MK maturation, proplatelet formation and platelet release (Schulze & Shivdasani 2004). NF-E2 deficient mice have profound thrombocytopenia (Shiraga et al. 1999). MYB (c-myb) functions with EP300 (p300) as a negative regulator of thrombopoiesis (Metcalf et al. 2005). During MK maturation, internal membrane systems, granules and organelles are assembled. Cytoplasmic fragmentation requires changes in the MK cytoskeleton and formation of organelles and channels. Individual organelles migrate from the cell body to the proplatelet ends, with approximately 30 percent of organelles/granules in motion at any given time (Richardson et al. 2005). View original pathway at Reactome.


Pathway is converted from Reactome ID: 983231
Reactome version: 75
Reactome Author 
Reactome Author: Akkerman, Jan Willem N

Quality Tags

Ontology Terms



View all...
  1. Goldfarb AN.; ''Transcriptional control of megakaryocyte development.''; PubMed Europe PMC Scholia
  2. Hirokawa N, Noda Y.; ''Intracellular transport and kinesin superfamily proteins, KIFs: structure, function, and dynamics.''; PubMed Europe PMC Scholia
  3. Levings PP, Bungert J.; ''The human beta-globin locus control region.''; PubMed Europe PMC Scholia
  4. Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS.; ''RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51.''; PubMed Europe PMC Scholia
  5. Yang X, Shears SB.; ''Multitasking in signal transduction by a promiscuous human Ins(3,4,5,6)P(4) 1-kinase/Ins(1,3,4)P(3) 5/6-kinase.''; PubMed Europe PMC Scholia
  6. Armstrong JA, Emerson BM.; ''NF-E2 disrupts chromatin structure at human beta-globin locus control region hypersensitive site 2 in vitro.''; PubMed Europe PMC Scholia
  7. Nielsen E, Christoforidis S, Uttenweiler-Joseph S, Miaczynska M, Dewitte F, Wilm M, Hoflack B, Zerial M.; ''Rabenosyn-5, a novel Rab5 effector, is complexed with hVPS45 and recruited to endosomes through a FYVE finger domain.''; PubMed Europe PMC Scholia
  8. Verhey KJ, Hammond JW.; ''Traffic control: regulation of kinesin motors.''; PubMed Europe PMC Scholia
  9. Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T.; ''Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins.''; PubMed Europe PMC Scholia
  10. Gery S, Cao Q, Gueller S, Xing H, Tefferi A, Koeffler HP.; ''Lnk inhibits myeloproliferative disorder-associated JAK2 mutant, JAK2V617F.''; PubMed Europe PMC Scholia
  11. Meller N, Irani-Tehrani M, Ratnikov BI, Paschal BM, Schwartz MA.; ''The novel Cdc42 guanine nucleotide exchange factor, zizimin1, dimerizes via the Cdc42-binding CZH2 domain.''; PubMed Europe PMC Scholia
  12. Tevosian SG, Deconinck AE, Cantor AB, Rieff HI, Fujiwara Y, Corfas G, Orkin SH.; ''FOG-2: A novel GATA-family cofactor related to multitype zinc-finger proteins Friend of GATA-1 and U-shaped.''; PubMed Europe PMC Scholia
  13. Nyman TA, Tölö H, Parkkinen J, Kalkkinen N.; ''Identification of nine interferon-alpha subtypes produced by Sendai virus-induced human peripheral blood leucocytes.''; PubMed Europe PMC Scholia
  14. Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R.; ''A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes.''; PubMed Europe PMC Scholia
  15. Lawrence CJ, Dawe RK, Christie KR, Cleveland DW, Dawson SC, Endow SA, Goldstein LS, Goodson HV, Hirokawa N, Howard J, Malmberg RL, McIntosh JR, Miki H, Mitchison TJ, Okada Y, Reddy AS, Saxton WM, Schliwa M, Scholey JM, Vale RD, Walczak CE, Wordeman L.; ''A standardized kinesin nomenclature.''; PubMed Europe PMC Scholia
  16. Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P.; ''Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange.''; PubMed Europe PMC Scholia
  17. Palombella VJ, Maniatis T.; ''Inducible processing of interferon regulatory factor-2.''; PubMed Europe PMC Scholia
  18. Hart MC, Korshunova YO, Cooper JA.; ''Vertebrates have conserved capping protein alpha isoforms with specific expression patterns.''; PubMed Europe PMC Scholia
  19. Rojo M, Legros F, Chateau D, Lombès A.; ''Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo.''; PubMed Europe PMC Scholia
  20. Lio YC, Mazin AV, Kowalczykowski SC, Chen DJ.; ''Complex formation by the human Rad51B and Rad51C DNA repair proteins and their activities in vitro.''; PubMed Europe PMC Scholia
  21. Kim SM, Kim JY, Choe NW, Cho IH, Kim JR, Kim DW, Seol JE, Lee SE, Kook H, Nam KI, Kook H, Bhak YY, Seo SB.; ''Regulation of mouse steroidogenesis by WHISTLE and JMJD1C through histone methylation balance.''; PubMed Europe PMC Scholia
  22. Tomasselli AG, Noda LH.; ''Mitochondrial GTP-AMP phosphotransferase. 2. Kinetic and equilibrium dialysis studies.''; PubMed Europe PMC Scholia
  23. Tsang AP, Visvader JE, Turner CA, Fujiwara Y, Yu C, Weiss MJ, Crossley M, Orkin SH.; ''FOG, a multitype zinc finger protein, acts as a cofactor for transcription factor GATA-1 in erythroid and megakaryocytic differentiation.''; PubMed Europe PMC Scholia
  24. Naslavsky N, Boehm M, Backlund PS, Caplan S.; ''Rabenosyn-5 and EHD1 interact and sequentially regulate protein recycling to the plasma membrane.''; PubMed Europe PMC Scholia
  25. Yang C, Pring M, Wear MA, Huang M, Cooper JA, Svitkina TM, Zigmond SH.; ''Mammalian CARMIL inhibits actin filament capping by capping protein.''; PubMed Europe PMC Scholia
  26. Wilson MP, Majerus PW.; ''Isolation of inositol 1,3,4-trisphosphate 5/6-kinase, cDNA cloning and expression of the recombinant enzyme.''; PubMed Europe PMC Scholia
  27. Miyamoto M, Fujita T, Kimura Y, Maruyama M, Harada H, Sudo Y, Miyata T, Taniguchi T.; ''Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements.''; PubMed Europe PMC Scholia
  28. Endow SA, Kull FJ, Liu H.; ''Kinesins at a glance.''; PubMed Europe PMC Scholia
  29. Vitali T, Maffioli E, Tedeschi G, Vanoni MA.; ''Properties and catalytic activities of MICAL1, the flavoenzyme involved in cytoskeleton dynamics, and modulation by its CH, LIM and C-terminal domains.''; PubMed Europe PMC Scholia
  30. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, Macara IG, Madhani H, Fink GR, Ravichandran KS.; ''Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex.''; PubMed Europe PMC Scholia
  31. Miyamoto Y, Yamauchi J, Sanbe A, Tanoue A.; ''Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth.''; PubMed Europe PMC Scholia
  32. Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS.; ''D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain.''; PubMed Europe PMC Scholia
  33. Huang LJ, Durick K, Weiner JA, Chun J, Taylor SS.; ''Identification of a novel protein kinase A anchoring protein that binds both type I and type II regulatory subunits.''; PubMed Europe PMC Scholia
  34. Mattei F, Schiavoni G, Tough DF.; ''Regulation of immune cell homeostasis by type I interferons.''; PubMed Europe PMC Scholia
  35. Nishikimi A, Meller N, Uekawa N, Isobe K, Schwartz MA, Maruyama M.; ''Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes.''; PubMed Europe PMC Scholia
  36. Deutsch VR, Tomer A.; ''Megakaryocyte development and platelet production.''; PubMed Europe PMC Scholia
  37. Chang Y, Bluteau D, Debili N, Vainchenker W.; ''From hematopoietic stem cells to platelets.''; PubMed Europe PMC Scholia
  38. Hiramoto K, Negishi M, Katoh H.; ''Dock4 is regulated by RhoG and promotes Rac-dependent cell migration.''; PubMed Europe PMC Scholia
  39. Escalante CR, Yie J, Thanos D, Aggarwal AK.; ''Structure of IRF-1 with bound DNA reveals determinants of interferon regulation.''; PubMed Europe PMC Scholia


View all...
114719view16:20, 25 January 2021ReactomeTeamReactome version 75
113164view11:23, 2 November 2020ReactomeTeamReactome version 74
112392view15:32, 9 October 2020ReactomeTeamReactome version 73
101296view11:18, 1 November 2018ReactomeTeamreactome version 66
100833view20:49, 31 October 2018ReactomeTeamreactome version 65
100374view19:24, 31 October 2018ReactomeTeamreactome version 64
99921view16:07, 31 October 2018ReactomeTeamreactome version 63
99476view14:40, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99130view12:40, 31 October 2018ReactomeTeamreactome version 62
93897view13:43, 16 August 2017ReactomeTeamreactome version 61
93470view11:24, 9 August 2017ReactomeTeamreactome version 61
87443view13:42, 22 July 2016MkutmonOntology Term : 'hemostasis pathway' added !
86564view09:21, 11 July 2016ReactomeTeamreactome version 56
83188view10:19, 18 November 2015ReactomeTeamVersion54
81558view13:05, 21 August 2015ReactomeTeamVersion53
77027view08:32, 17 July 2014ReactomeTeamFixed remaining interactions
76732view12:09, 16 July 2014ReactomeTeamFixed remaining interactions
76057view10:12, 11 June 2014ReactomeTeamRe-fixing comment source
75767view11:27, 10 June 2014ReactomeTeamReactome 48 Update
75117view14:06, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74764view08:51, 30 April 2014ReactomeTeamReactome46
42038view21:52, 4 March 2011MaintBotAutomatic update
39841view05:52, 21 January 2011MaintBotNew pathway

External references


View all...
NameTypeDatabase referenceComment
ABL1 ProteinP00519 (Uniprot-TrEMBL)
ABL1ProteinP00519 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
AK3ProteinQ9UIJ7 (Uniprot-TrEMBL)
AKAP1 ProteinQ92667 (Uniprot-TrEMBL)
AKAP10 ProteinO43572 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)


DNA binding sites
ComplexR-HSA-996764 (Reactome)
BHC complexComplexR-HSA-4657016 (Reactome)

EH domain containing

ComplexR-HSA-1011577 (Reactome)
C-terminal EH domain containing proteinsComplexR-HSA-1011595 (Reactome)
CABLES1 ProteinQ8TDN4 (Uniprot-TrEMBL)
CABLES1ProteinQ8TDN4 (Uniprot-TrEMBL)
CABLES2 ProteinQ9BTV7 (Uniprot-TrEMBL)
CABLESComplexR-HSA-1013880 (Reactome)
CAPZA1 ProteinP52907 (Uniprot-TrEMBL)
CAPZA2 ProteinP47755 (Uniprot-TrEMBL)
CAPZB ProteinP47756 (Uniprot-TrEMBL)
CAPZBProteinP47756 (Uniprot-TrEMBL)
CBX5 ProteinP45973 (Uniprot-TrEMBL)
CBX5ProteinP45973 (Uniprot-TrEMBL)
CDC42 ProteinP60953 (Uniprot-TrEMBL)
CDK2 ProteinP24941 (Uniprot-TrEMBL)
CDK2:CABLES1:WEE1ComplexR-HSA-1013858 (Reactome)
CDK2ProteinP24941 (Uniprot-TrEMBL)
CDK5 ProteinQ00535 (Uniprot-TrEMBL)
CDK5:CABLES:ABLComplexR-HSA-1013836 (Reactome)
CDK5ProteinQ00535 (Uniprot-TrEMBL)
DOCK-GEFs:RAC1, CDC42ComplexR-HSA-1012969 (Reactome)
DOCK-GEFsComplexR-HSA-1012978 (Reactome)
DOCK1 ProteinQ14185 (Uniprot-TrEMBL)
DOCK10 ProteinQ96BY6 (Uniprot-TrEMBL)
DOCK11 ProteinQ5JSL3 (Uniprot-TrEMBL)
DOCK2 ProteinQ92608 (Uniprot-TrEMBL)
DOCK3 ProteinQ8IZD9 (Uniprot-TrEMBL)
DOCK4 ProteinQ8N1I0 (Uniprot-TrEMBL)
DOCK5 ProteinQ9H7D0 (Uniprot-TrEMBL)
DOCK6 ProteinQ96HP0 (Uniprot-TrEMBL)
DOCK7 ProteinQ96N67 (Uniprot-TrEMBL)
DOCK8 ProteinQ8NF50 (Uniprot-TrEMBL)
DOCK9 ProteinQ9BZ29 (Uniprot-TrEMBL)
Dual-specific AKAPs:PKA tetramerComplexR-HSA-992693 (Reactome)
Dual-specific AKAPsComplexR-HSA-992722 (Reactome)
EHD1 ProteinQ9H4M9 (Uniprot-TrEMBL)
EHD2 ProteinQ9NZN4 (Uniprot-TrEMBL)
EHD3 ProteinQ9NZN3 (Uniprot-TrEMBL)
F-actin capping

protein alpha

ComplexR-HSA-879442 (Reactome)
F-actin capping protein:f-actinComplexR-HSA-994173 (Reactome)
F-actin capping proteinComplexR-HSA-879384 (Reactome)
FAD MetaboliteCHEBI:16238 (ChEBI)
GATA proteinsComplexR-HSA-996770 (Reactome)
GATA1 ProteinP15976 (Uniprot-TrEMBL)
GATA2 ProteinP23769 (Uniprot-TrEMBL)
GATA3 ProteinP23771 (Uniprot-TrEMBL)
GATA4 ProteinP43694 (Uniprot-TrEMBL)
GATA5 ProteinQ9BWX5 (Uniprot-TrEMBL)
GATA6 ProteinQ92908 (Uniprot-TrEMBL)
GDPMetaboliteCHEBI:17552 (ChEBI)
GTPMetaboliteCHEBI:15996 (ChEBI)
Globin genesComplexR-HSA-9605269 (Reactome)
H2O2MetaboliteCHEBI:16240 (ChEBI)
HBB gene ProteinENSG00000244734 (Ensembl)
HBBProteinP68871 (Uniprot-TrEMBL)
HBD gene ProteinENSG00000223609 (Ensembl)
HBDProteinP02042 (Uniprot-TrEMBL)
HBE1 gene ProteinENSG00000213931 (Ensembl)
HBE1ProteinP02100 (Uniprot-TrEMBL)
HBG1 gene ProteinENSG00000213934 (Ensembl)
HBG1ProteinP69891 (Uniprot-TrEMBL)
HBG2 gene ProteinENSG00000196565 (Ensembl)
HBG2ProteinP69892 (Uniprot-TrEMBL)
HDAC1 ProteinQ13547 (Uniprot-TrEMBL)
HDAC2 ProteinQ92769 (Uniprot-TrEMBL)
HMG20B ProteinQ9P0W2 (Uniprot-TrEMBL)
HP1alpha:Histone H3 methylated at K9ComplexR-HSA-994100 (Reactome)
Histone H3

methylated at

ComplexR-HSA-427391 (Reactome)
Histone H3 R-HSA-212293 (Reactome)
Histone H3 dimethylated at lysine-9 R-HSA-427406 (Reactome)
Histone H3 methylated at lysine-9 R-HSA-427391 (Reactome)
Histone H3 mono or di-methylated at K9ComplexR-HSA-997256 (Reactome)
Histone H3 mono- or unmethylated at K9ComplexR-HSA-997233 (Reactome)
I(1,3,4)P3MetaboliteCHEBI:18228 (ChEBI)
I(1,3,4,5)P4MetaboliteCHEBI:16783 (ChEBI)
I(1,3,4,5,6)P5MetaboliteCHEBI:16322 (ChEBI)
I(1,3,4,6)P4MetaboliteCHEBI:16155 (ChEBI)
I(3,4,5,6)P4MetaboliteCHEBI:15844 (ChEBI)
IFN alpha/beta (IFNA/B)ComplexR-HSA-909690 (Reactome)
IFNA R-HSA-909688 (Reactome)
IFNA genes R-HSA-9038682 (Reactome)
IFNA genesComplexR-HSA-9038682 (Reactome)
IFNA1 gene ProteinENSG00000233816 (Ensembl)
IFNA10 gene ProteinENSG00000186803 (Ensembl)
IFNA14 gene ProteinENSG00000228083 (Ensembl)
IFNA16 gene ProteinENSG00000147885 (Ensembl)
IFNA17 gene ProteinENSG00000234829 (Ensembl)
IFNA2 gene ProteinENSG00000188379 (Ensembl)
IFNA21 gene ProteinENSG00000137080 (Ensembl)
IFNA4 gene ProteinENSG00000236637 (Ensembl)
IFNA5 gene ProteinENSG00000147873 (Ensembl)
IFNA6 gene ProteinENSG00000120235 (Ensembl)
IFNA7 gene ProteinENSG00000214042 (Ensembl)
IFNA8 gene ProteinENSG00000120242 (Ensembl)
IFNB1 ProteinP01574 (Uniprot-TrEMBL)
IFNB1 gene ProteinENSG00000171855 (Ensembl)
IFNB1 geneGeneProductENSG00000171855 (Ensembl)
IRF1 ProteinP10914 (Uniprot-TrEMBL)
IRF1:Promotors of IFN alpha, IFN betaComplexR-HSA-1008247 (Reactome)
IRF1ProteinP10914 (Uniprot-TrEMBL)
IRF2 ProteinP14316 (Uniprot-TrEMBL)
IRF2:promoters of INF alpha, INF betaComplexR-HSA-1018386 (Reactome)
IRF2ProteinP14316 (Uniprot-TrEMBL)
ITPK1ProteinQ13572 (Uniprot-TrEMBL)
JMJD1CProteinQ15652 (Uniprot-TrEMBL)
KDM1A ProteinO60341 (Uniprot-TrEMBL)
KinesinsPathwayR-HSA-983189 (Reactome) Kinesins are a superfamily of microtubule-based motor proteins that have diverse functions in transport of vesicles, organelles and chromosomes, and regulate microtubule dynamics. There are 14 families of kinesins, all reprsented in humans. A standardized nomenclature was published in 2004 (Lawrence et al.).
LRRC16A ProteinQ5VZK9 (Uniprot-TrEMBL)
LRRC16A:F-actin capping proteinComplexR-HSA-994154 (Reactome)
LRRC16AProteinQ5VZK9 (Uniprot-TrEMBL)
MAFF ProteinQ9ULX9 (Uniprot-TrEMBL)
MAFG ProteinO15525 (Uniprot-TrEMBL)
MAFK ProteinO60675 (Uniprot-TrEMBL)
MFN1 ProteinQ8IWA4 (Uniprot-TrEMBL)
MFN2 ProteinO95140 (Uniprot-TrEMBL)
MICAL1 ProteinQ8TDZ2 (Uniprot-TrEMBL)
MICAL1:FADComplexR-HSA-8868407 (Reactome)
MYB ProteinP10242 (Uniprot-TrEMBL)
MYBProteinP10242 (Uniprot-TrEMBL)
MeK-H3F3A ProteinP84243 (Uniprot-TrEMBL)
MeK-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
MeK10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Mitofusin complexComplexR-HSA-992739 (Reactome)
MitofusinsComplexR-HSA-992720 (Reactome)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)

region of

ComplexR-HSA-1008206 (Reactome)
NF-E2ComplexR-HSA-1008229 (Reactome)
NFE2 ProteinQ16621 (Uniprot-TrEMBL)
NFE2ProteinQ16621 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PHF21A ProteinQ96BD5 (Uniprot-TrEMBL)
PKA tetramerComplexR-HSA-111922 (Reactome)
PRKACA ProteinP17612 (Uniprot-TrEMBL)
PRKACB ProteinP22694 (Uniprot-TrEMBL)
PRKACG ProteinP22612 (Uniprot-TrEMBL)
PRKAR1A ProteinP10644 (Uniprot-TrEMBL)
PRKAR1B ProteinP31321 (Uniprot-TrEMBL)
PRKAR2A ProteinP13861 (Uniprot-TrEMBL)
PRKAR2B ProteinP31323 (Uniprot-TrEMBL)
Promotor region of beta-globinR-ALL-1008228 (Reactome)
Promotor region of beta-globin R-ALL-1008228 (Reactome)
RAB5A ProteinP20339 (Uniprot-TrEMBL)
RAB5AProteinP20339 (Uniprot-TrEMBL)
RAC1 ProteinP63000 (Uniprot-TrEMBL)
RAC1, CDC42ComplexR-HSA-1012988 (Reactome)
RAD51B ProteinO15315 (Uniprot-TrEMBL)
RAD51B:RAD51C:Single-stranded DNAComplexR-HSA-983270 (Reactome)
RAD51B:RAD51CComplexR-HSA-983240 (Reactome)
RAD51BProteinO15315 (Uniprot-TrEMBL)
RAD51C ProteinO43502 (Uniprot-TrEMBL)
RAD51CProteinO43502 (Uniprot-TrEMBL)
RCOR1 ProteinQ9UKL0 (Uniprot-TrEMBL)
REST DNA binding sites R-ALL-996771 (Reactome)
REST:REST DNA binding sitesComplexR-HSA-996761 (Reactome)
Rabenosyn-5:VPS-45ComplexR-HSA-1011605 (Reactome)
SH2B family:p-Y813-JAK2ComplexR-HSA-997243 (Reactome)
SH2B familyComplexR-HSA-997265 (Reactome)
SH2B1 ProteinQ9NRF2 (Uniprot-TrEMBL)
SH2B2 ProteinO14492 (Uniprot-TrEMBL)
SH2B3 ProteinQ9UQQ2 (Uniprot-TrEMBL)
SIN3A ProteinQ96ST3 (Uniprot-TrEMBL)
SIN3AProteinQ96ST3 (Uniprot-TrEMBL)
Single-stranded DNA MetaboliteCHEBI:9160 (ChEBI)
Single-stranded DNAMetaboliteCHEBI:9160 (ChEBI)
Small Maf family membersComplexR-HSA-1008234 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
Type-I IFN genesComplexR-HSA-1027363 (Reactome)
VPS45 ProteinQ9NRW7 (Uniprot-TrEMBL)
VPS45ProteinQ9NRW7 (Uniprot-TrEMBL)
WEE1 ProteinP30291 (Uniprot-TrEMBL)
WEE1ProteinP30291 (Uniprot-TrEMBL)
ZFPM proteins:GATA proteinsComplexR-HSA-996751 (Reactome)
ZFPM1 ProteinQ8IX07 (Uniprot-TrEMBL)
ZFPM1, ZFPM2ComplexR-HSA-996742 (Reactome)
ZFPM2 ProteinQ8WW38 (Uniprot-TrEMBL)
ZFYVE20 ProteinQ9H1K0 (Uniprot-TrEMBL)
ZFYVE20ProteinQ9H1K0 (Uniprot-TrEMBL)
adenosine 5'-monophosphateMetaboliteCHEBI:16027 (ChEBI)
f-actin R-HSA-994160 (Reactome)
f-actinR-HSA-994160 (Reactome)
p-Y813-JAK2 ProteinO60674 (Uniprot-TrEMBL)
p-Y813-JAK2ProteinO60674 (Uniprot-TrEMBL)
p53:MYB:SIN3AComplexR-HSA-992748 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ABL1R-HSA-1013833 (Reactome)
ADPArrowR-HSA-1008248 (Reactome)
ADPArrowR-HSA-2267372 (Reactome)
ADPArrowR-HSA-994137 (Reactome)
ADPArrowR-HSA-994140 (Reactome)
AK3mim-catalysisR-HSA-1008248 (Reactome)
ATPR-HSA-2267372 (Reactome)
ATPR-HSA-994137 (Reactome)
ATPR-HSA-994140 (Reactome)


DNA binding sites
ArrowR-HSA-996727 (Reactome)
BHC complexR-HSA-996727 (Reactome)

EH domain containing

ArrowR-HSA-1011576 (Reactome)
C-terminal EH domain containing proteinsR-HSA-1011576 (Reactome)
CABLES1R-HSA-1013881 (Reactome)
CABLESR-HSA-1013833 (Reactome)
CAPZBR-HSA-879459 (Reactome)
CBX5R-HSA-994106 (Reactome)
CDK2:CABLES1:WEE1ArrowR-HSA-1013881 (Reactome)
CDK2R-HSA-1013881 (Reactome)
CDK5:CABLES:ABLArrowR-HSA-1013833 (Reactome)
CDK5R-HSA-1013833 (Reactome)
DOCK-GEFs:RAC1, CDC42ArrowR-HSA-1011598 (Reactome)
DOCK-GEFsR-HSA-1011598 (Reactome)
Dual-specific AKAPs:PKA tetramerArrowR-HSA-992708 (Reactome)
Dual-specific AKAPsR-HSA-992708 (Reactome)
F-actin capping

protein alpha

R-HSA-879459 (Reactome)
F-actin capping protein:f-actinArrowR-HSA-994169 (Reactome)
F-actin capping proteinArrowR-HSA-879459 (Reactome)
F-actin capping proteinR-HSA-994148 (Reactome)
F-actin capping proteinR-HSA-994169 (Reactome)
GATA proteinsR-HSA-996755 (Reactome)
GDPArrowR-HSA-1008248 (Reactome)
GTPR-HSA-1008248 (Reactome)
Globin genesR-HSA-1008220 (Reactome)
H2O2ArrowR-HSA-8865107 (Reactome)
HBBArrowR-HSA-1008220 (Reactome)
HBDArrowR-HSA-1008220 (Reactome)
HBE1ArrowR-HSA-1008220 (Reactome)
HBG1ArrowR-HSA-1008220 (Reactome)
HBG2ArrowR-HSA-1008220 (Reactome)
HP1alpha:Histone H3 methylated at K9ArrowR-HSA-994106 (Reactome)
Histone H3

methylated at

R-HSA-994106 (Reactome)
Histone H3 mono or di-methylated at K9R-HSA-997263 (Reactome)
Histone H3 mono- or unmethylated at K9ArrowR-HSA-997263 (Reactome)
I(1,3,4)P3R-HSA-2267372 (Reactome)
I(1,3,4)P3R-HSA-994140 (Reactome)
I(1,3,4,5)P4ArrowR-HSA-994140 (Reactome)
I(1,3,4,5,6)P5ArrowR-HSA-994137 (Reactome)
I(1,3,4,6)P4ArrowR-HSA-2267372 (Reactome)
I(3,4,5,6)P4R-HSA-994137 (Reactome)
IFN alpha/beta (IFNA/B)ArrowR-HSA-994034 (Reactome)
IFNA genesR-HSA-994020 (Reactome)
IFNA genesR-HSA-994038 (Reactome)
IFNB1 geneR-HSA-994020 (Reactome)
IFNB1 geneR-HSA-994038 (Reactome)
IRF1:Promotors of IFN alpha, IFN betaArrowR-HSA-994020 (Reactome)
IRF1:Promotors of IFN alpha, IFN betaArrowR-HSA-994034 (Reactome)
IRF1R-HSA-994020 (Reactome)
IRF2:promoters of INF alpha, INF betaArrowR-HSA-994038 (Reactome)
IRF2:promoters of INF alpha, INF betaTBarR-HSA-994034 (Reactome)
IRF2R-HSA-994038 (Reactome)
ITPK1mim-catalysisR-HSA-2267372 (Reactome)
ITPK1mim-catalysisR-HSA-994137 (Reactome)
ITPK1mim-catalysisR-HSA-994140 (Reactome)
JMJD1Cmim-catalysisR-HSA-997263 (Reactome)
LRRC16A:F-actin capping proteinArrowR-HSA-994148 (Reactome)
LRRC16AR-HSA-994148 (Reactome)
MICAL1:FADmim-catalysisR-HSA-8865107 (Reactome)
MYBR-HSA-992696 (Reactome)
Mitofusin complexArrowR-HSA-992703 (Reactome)
MitofusinsR-HSA-992703 (Reactome)
NADP+ArrowR-HSA-8865107 (Reactome)
NADPHR-HSA-8865107 (Reactome)

region of

ArrowR-HSA-1008200 (Reactome)

region of

ArrowR-HSA-1008220 (Reactome)
NF-E2ArrowR-HSA-1008240 (Reactome)
NF-E2R-HSA-1008200 (Reactome)
NFE2R-HSA-1008240 (Reactome)
O2R-HSA-8865107 (Reactome)
PKA tetramerR-HSA-992708 (Reactome)
Promotor region of beta-globinR-HSA-1008200 (Reactome)
R-HSA-1008200 (Reactome) The human beta-globin locus control region (LCR) controls expression of the beta-globin gene family. It consists of four erythroid-cell-specific DNase I hypersensitive sites, HS1-4. DNAse I HS sites are thought to represent nucleosome-free regions of DNA which are available to trans-acting factors. NF-E2 binds two tandem AP1-like sites in HS2 which form the core of its enhancer activity. Interaction of NF-E2 with HS2 allows a second erythroid factor, GATA-1, to bind its nearby sites.
R-HSA-1008220 (Reactome) The human beta-globin locus consists of five genes encoding the beta globin gene but also delta, gamma-A, gamma-G and epsilon globin. All of these genes are controlled by the beta globin locus control region.
R-HSA-1008240 (Reactome) NF-E2 is a heterodimer consisting of a hematopoietic-specific subunit NFE2-p45, a member of the cap and collar (CNC) family, and a more widely expressed small subunit which can be any of the three small members of the Maf protein family MafF, MafG OR MafK (Motohashi et al. 1997). MafG and MafK are the predominant small Maf molecules in erythroid cells and megakaryocytes (Shavit et al. 1998).

NF-E2 binds to an extended AP-1-like element, TGCTGA(G/C)TCA, which is found in the locus control regions (LCRs) of the alpha- and beta-globin genes and in the promoters of several heme biosynthetic enzyme genes (see Motohashi et al. 1997). NF-E2 binding sites in the DNase I hypersensitive site 2 (HS2) of the beta-globin LCR are essential for its enhancer activity (Ney et al. 1990, Talbot & Grosveld 1991).

NFE2-p45 null mice have a mild defect in globin gene expression, suggesting that other members of the CNC protein family can substitute for function in vivo (Shivdasani & Orkin 1995).
R-HSA-1008248 (Reactome) GTP-AMP phosphotransferase, also called Adenylate kinase 3 catalyzes phosphate transfer from GTP to AMP (EC A crystal structure is available (Choe et al. 2005).
R-HSA-1011576 (Reactome) The four human EH domain-containing proteins (EHD1-4) are a distinct highly-homologous subfamily of the Eps15-homology (EH) domain family. They are distinct from most other EH family members in having the EH-domain at the C-terminus (Naslavsky & Caplan 2005). EH domains interact with other proteins; peptides containing Asp-Pro-Phe (NPF) motifs are major targets for EH-domain binding (Salcini et al. 1997).

EH domain family proteins have regulatory roles in endocytic membrane transport events (Naslavsky & Caplan 2005); the EHD subfamily is believed to regulate endocytic recycling (George et al. 2007). All four human EHD proteins can rescue the vacuolated intestinal phenotype observed when the C. elegans orthologue rme-1 is mutated (George et al. 2007).

Over 20 interaction partners have been reported for the C-terminal EHD proteins including clathirin, syndaptins and Arp2/3 (see Naslavsky & Caplan 2005). EHD1-3 all interact with Rabenosyn-5 (Rab5), a Rab5 effector (Naslavsky et al. 2004).
R-HSA-1011598 (Reactome) Members of the Dedicator of cytokinesis (DOCK) family, also known as the Dock180 superfamily, are Rho GTPase guanine nucleotide exchange factors (GEFs), modulating Rho GTPase activity (Cote & Vuori 2002). All eleven human members share the presence of two evolutionarily conserved protein domains, termed DHR-1 and DHR-2 (Cote & Vuori 2007). The DHR-2 domains of several DOCKs interact with the nucleotide-free forms of Rho GTPases, intermediates in the catalytic reaction leading to the exchange of GDP for GTP. DHR-2 domains have been shown necessary and sufficient to promote specific guanine nucleotide exchange on various Rho GTPases, both in vitro and in vivo. Inactivation of the DHR-2 domain in DOCK1 (Dock180) has been shown to block Rac activation, cell migration and phagocytosis (Brugnera et al. 2002, Grimsley et al. 2004, Cote & Vuori 2002). The DHR-1 domain of DOCK1 was shown to mediate a specific interaction with PIP2 and PIP3 signaling lipids in vitro and in cells (Cote et al. 2005). Mutations of the DOCK1 DHR-1 domain blocked Rac-dependent cell elongation and cell migration suggesting that the role of DHR-1 is to position DOCK1 at sites of PIP3 production by PI3-kinase, coupling this to Rac signaling (Cote & Vuori 2007).
R-HSA-1011600 (Reactome) The small GTPase Rab5 regulates membrane traffic into and between early endosomes by specifically recruiting cytosolic effector proteins to their site of action on early endosomal membranes. Rab5 occupies a restricted membrane subdomain on endosomes that has distinct biochemical features when compared with neighboring subcompartments (Sonnichsen et al. 2000). Rab5 is believed to form this subdomain by recruiting the specific PI3 kinase VPS-45, causing localized production of PI-3-phosphate (PI-3P) (Christoforidis et al. 1999). Rabenosyn-5 is a Rab5 effector, recruited in a phosphatidylinositol-3-kinase dependent fashion to early endosomes where it serves as a molecular link between VPS-45 and Rab5.
R-HSA-1013833 (Reactome) CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In neurons, Cables1 links Cdk5 and c-Abl, enhancing Cdk5 tyrosine-15 phosphorylation which results in increased Cdk5 activity, important in neurite outgrowth (Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity, Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002).
R-HSA-1013881 (Reactome) CDK5 and ABL1 enzyme substrate 1 (Cables1) is a negative regulator of cell proliferation. Loss of Cables1 function can lead to uncontrolled growth in vivo, observed in many human cancers, such as colon, lung and gynecological malignancies including ovarian and endometrial cancers (Sakamoto et al. 2008). Cables1 is up-regulated by progesterone and down-regulated by estrogen (Zukerberg et al. 2004). Cables1 is predominantly located in the nucleus of proliferating cells (Zukerberg et al. 2000, Wu et al. 2001) but some fully differentiated cells such as mature neurons have a significant proportion in the cytoplasm. Cables1 interacts with cyclin-dependent kinases (Cdk) 2, 3 and 5 (Wu et al. 2001, Matsuoka et al. 2000, Zukerberg et al. 2000). In proliferating cells, Cables1 links Cdk2 and Wee1, a dual specificity kinase. Phosphorylation of Cdk2 on tyrosine-15 by Wee-1 leads to decreased Cdk2 activity; Cables1 enhances this inhibitory phosphorylation (Wu et al. 2001). Cables1 has also been shown to interact with two regulators of apoptosis, p53 and p73. The physiological relevance of this interaction is not fully understood, but Cables1 augments p53-induced apoptosis in human osteosarcoma cells (Tsuji et al. 2002). Cables2 interacts with Cdk3, Cdk5 and c-Abl (Sato et al. 2002).
R-HSA-2267372 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-6 to form Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway.
R-HSA-879459 (Reactome) F-actin-capping protein binds in a Ca2+-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits. Unlike other capping proteins (such as gelsolin and severin), they do not sever actin filaments.
R-HSA-8865107 (Reactome) MICAL1 is involved in cytoskeleton dynamics through its NADPH-dependent oxidase and F-actin depolymerizing activities. MICAL1 inhibits actin polymerization and promotes actin depolymerization (Hung et al. 2011). F-actin is thought to bind and stabilize the flavoprotein domain in MICAL's active conformation (Kolk & Pasterkamp 2007). Actin depolymerization mediated by MICAL1 is thought to be a consequence of H2O2 produced by MICAL1 NADPH oxidase activity (Nadella et al. 2005, Zucchini et al. 2011), rather than due to direct hydroxylation of actin methionine residues (Vitali et al. 2016).
R-HSA-983218 (Reactome) The complex of Rad51B and Rad51C binds single-stranded DNA and hydrolyses ATP (Sigurdsson et al. 2001). Rad51B and Rad51C are both required for recombination and DNA double-strand break repair in vivo. The complex cannot substitute for RPA but enhances Rad51/RPA mediated repair. The proposed mechanism for this is that Rad51b:Rad51C partially overcomes the suppressive effect of RPA on Rad51-catalyzed DNA pairing and strand exchange; RPA is an important accessory factor for Rad51-mediated homologous DNA pairing and strand exchange, but it can also compete with Rad51 for binding sites on the ssDNA template, which, when allowed to occur, suppresses pairing and strand exchange efficiency markedly (Sung et al. 2000).
R-HSA-983285 (Reactome) The Rad51-like proteins Rad51B and Rad51C form a highly stable complex. This complex assists Rad51 in the early stages of homologous recombination.
R-HSA-992696 (Reactome) The DNA-binding domain of c-Myb binds the co-repressor protein SIN3A (Nomura et al. 2004). The tumor repressor p53 also binds MYB directly (Tanikawa et al. 2004), promoting formation of a trimeric SIN3A:c-Myb:p53 complex. This does not affect the ability of c-Myb to bind to DNA, but may represent the mechanism that allows p53 to to regulate specific Myb target genes.
c-Myb (gene symbol MYB) is highly conserved in all vertebrates and some invertebrate species (Lipsick 1996). It plays an important role in the control of proliferation and differentiation of hematopoietic progenitor cells (Duprey & Boettiger 1985); Down-regulation of c-Myb is believed to be critical for the commitment of cells to terminal differentiation (Oh & Reddy, 1999). c-Myb interacts with many other transcription factors including CBP, several CCAAT binding protein (c/EBP) family members, and Ets family proteins such as Ets-2 (Oh & Reddy, 1999).
Loss of c-Myb function results in embryonic lethality due to failure of fetal hepatic hematopoiesis (Mucenski et al. 1991).
R-HSA-992703 (Reactome) Mitochondria frequently fuse and divide (Bereiter-Hahn & Voth 1994); these processes affect morphology and are important for normal mitochondrial functions such as respiration, development and apoptosis. Mitofusins (MFNs) are mitochondrial GTPases that mediate mitochondrial outer membrane fusion. Mammals have two mitofusins; Mfn1-null or Mfn2-null mouse embryonic fibroblast cells show predominantly fragmented mitochondria and have greatly reduced mitochondrial fusion in vivo (Chen et al. 2003, 2005). MFNs acts in trans to bring mitochondria into close proximity prior to fusion (Koshiba et al. 2004). They also tether the endoplasmic reticulum (ER) to mitochondria, cross-linking MFNs expressed on the mitochondrial outer membrane and ER membrane (de Brito & Scorrano 2008).
R-HSA-992708 (Reactome) Protein kinase A (PKA) refers to a family of multimeric enzyme complexes whose activity is dependent on the level of cyclic AMP (cAMP), hence PKA is also known as cAMP-dependent protein kinase (EC PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. PKA is a holoenzyme complex consisting of two regulatory and two catalytic subunits. When cAMP levela are low the holoenzyme remains intact and is inactive. When the concentration of cAMP rises (e.g. as a result of adenylate cyclase activation by G protein-coupled receptors coupled to Gs, or inhibition of phosphodiesterases that degrade cAMP) cAMP binds to two binding sites on the regulatory subunits, leading to the release and activation of the catalytic subunits. The regulatory subunits of PKA are also important for localizing the kinase inside the cell. A-kinase anchor proteins (AKAPs) bind to the regulatory subunits and to cytoskeletal structures or membranes, anchoring the enzyme complex to a particular subcellular compartment. Dual-specificity A kinase-anchoring proteins (AKAP1/D-AKAP1) and (AKAP10/D-AKAP2) interact with the type I and type II regulatory subunits of PKA (Huang et al. 1997). AKAP10 additionally has two regulator of G-protein signaling (RGS) domains, giving it the potential to coordinate a signaling complex that links cAMP signaling with G-protein-coupled receptor (GPCR) signaling (Burns-Hamuro et al. 2004).
R-HSA-994020 (Reactome) Interferon regulatory factor-1 (IRF-1) is a positive transcription factor for genes involved in immune response, cell growth regulation and apoptosis in mammalian cells. Many agents such as viruses, interferon (IFN), double-stranded RNA (dsRNA), and proinflammatory cytokines induce IRF-1 transcription. IRF-1 transcriptionally activates many IRF-1-regulated genes during normal physiological and pathological conditions, including interferon-beta and alpha (Escalante et al. 1998, Harada et al. 1990), iNOS, COX-2, VCAM-1, IL-12, IL-15, CIITA, Caspase-1 and Caspase-7 (Upreti & Rath 2005).
R-HSA-994034 (Reactome) The Interferon alpha and beta genes are transcribed and translated yielding IFNA and IFNB which are secreted. This process is positively regulated by Interferon Regulatory Factor 1 and negatively regulated by Interferon Regulatory Factor 2, which compete for binding to the same regulatory element (Harada et al. 1989).
R-HSA-994038 (Reactome) Interferon regulatory factor 2 (IRF-2) represses the action of IRF-1 on type I interferon genes (Harada et al, 1989, 1990; Palombella & Maniatis, 1992) by competing with IRF-1 for binding at the PRDI site.
R-HSA-994106 (Reactome) Chromobox (CBX) genes encode members of the Heterochromatin Protein (HP) family. HP1 was discovered in Drosophila as a dominant suppressor of position-effect variegation and a major component of heterochromatin. The HP1 family is evolutionarily conserved, with members in fungi, plants and animals. Most animal species have several HP1 isoforms; humans have HP alpha, beta and gamme encoded by the genes CBX5, CBX1 and CBX3 respectively.
The HP1 amino-terminal chromodomain binds methylated lysine-9 of histone H3, causing transcriptional repression (Lachner et al. 2001). A crystal structure of human HP1 alpha in complex with H3K9(me)3 peptide is available (Amaya et al. 2008). The highly-conserved carboxy-terminal chromoshadow domain enables dimerization and also serves as a docking site for proteins involved in a wide variety of nuclear functions, from transcription to nuclear architecture.

R-HSA-994137 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) can phosphorylate inositol polyphosphates Ins(3,4,5,6)P4 at position 1 to form Ins(1,3,4,5,6)P5. This reaction is thought to have regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca2+-activated Cl- channels.
R-HSA-994140 (Reactome) Inositol-tetrakisphosphate 1-kinase (ITPK1) phosphorylates Ins(1,3,4)P3 on O-5 to form Ins(1,3,4,5)P4.
R-HSA-994148 (Reactome) Leucine rich repeat-containing protein 16A (CARMIL homolog) binds F-actin capping protein (CP) with high affinity, significantly decreasing the affinity of CP for actin barbed ends. Actin polymerization occurs at the barbed end; proteins like CP that cap the barbed end inhibit elongation. Inhibition of CP therefore enhances the rate of barbed-end actin polymerization. In cells, GFP-LRRC16A was seen to be concentrated in lamellipodia and increased the fraction of cells with large lamellipodia. Decreasing LRRC16A levels with siRNA lowered F-actin levels, decreased lamellipodia protrusion and slowed cell migration.
R-HSA-994169 (Reactome) Actin capping protein (CP) was named for its ability to bind the barbed ends of actin filaments. CP inhibits the addition and loss of actin subunits at the barbed end and is important for the dynamics of actin filament assembly, and therefore important for the control of cell shape and movement. CP was called beta-actinin when first characterized and purified from muscle (Maruyama 1966). Actin polymerization is controlled by a large cellular excess of capping proteins which bind to the barbed end of actin filaments preventing elongation.
R-HSA-996727 (Reactome) The BHC (BRAF-HDAC) complex is involved in the repression of neuronal-specific genes during development. It is recruited by RE1-silencing transcription factor (REST) to mediate the repression of REST-responsive genes. The BHC complex includes histone deacetylases (HDACs) 1 and 2, and the histone demethylase KDM1A (also knowns as BHC110, LSD1 or AOF2). KDM1A demethylates both Lys-4 (H3K4me) and Lys-9 (H3K9me) of histone H3, acting as a coactivator or a corepressor, depending on the context. Corepressor for element-1-silencing transcription factor (CoREST) is an essential component of the BHC complex, enhancing the association with nucleosomes (Lee et al. 2005).

REST is a modular transcriptional regulator that recruits CoREST and other regulatory cofactors to activate or repress transcription through dynamic epigenetic mechanisms (Ballas & Mandel 2005).
R-HSA-996755 (Reactome) The Friend of GATA (FOG) family of proteins are a highly-conserved family of large multitype zinc finger cofactors that bind to the amino zinc finger of GATA transcription factors, modulating their activity. GATA proteins are named for the DNA consensus sequence they recognize, (T/A)GATA(A/G). FOG/GATA protein interactions are essential for the development of many tissues. All six GATA family members are capable of interacting with both FOG-1 and FOG-2 (Tsang et al. 1997, Tevosian et al. 1999). Mutations that disrupt binding of GATA-1 to FOG-1 are associated with a syndrome of severe X-linked macrothrombocytopenia (Cantor & Orkin 2005) and in some cases dyserythropoietic anemia (Nichols et al. 2000). In addition to binding GAG proteins, FOGs interact with complexes containing the co-repressor C-terminal binding protein (CtBP) that are thought to coordinate histone modifications leading to a transcriptionally repressed state (Shi et al. 2003).
R-HSA-997237 (Reactome) The SH2B family has 3 members sharing a common domain structure, including a dimerization domain, a pleckstrin homology (PH) region, and a SH2 domain. The SH2 domain binds phosphotyrosines of various signal-transducing proteins such as c-Kit, MPL, EpoR. All are able to bind JAK2 phosphorylated at Tyr-813 (Bersenev et al. 2008, Kurzer et al. 2004, 2006), inhibiting JAK2 proliferative signaling (Gery et al. 2009).
R-HSA-997263 (Reactome) JMJD1C specifically demethylates histone H3K9 mono- and di-methylation, thereby mediating transcriptional activation.
RAB5AR-HSA-1011600 (Reactome)
RAC1, CDC42R-HSA-1011598 (Reactome)
RAD51B:RAD51C:Single-stranded DNAArrowR-HSA-983218 (Reactome)
RAD51B:RAD51CArrowR-HSA-983285 (Reactome)
RAD51B:RAD51CR-HSA-983218 (Reactome)
RAD51BR-HSA-983285 (Reactome)
RAD51CR-HSA-983285 (Reactome)
REST:REST DNA binding sitesR-HSA-996727 (Reactome)
Rabenosyn-5:VPS-45ArrowR-HSA-1011600 (Reactome)
SH2B family:p-Y813-JAK2ArrowR-HSA-997237 (Reactome)
SH2B familyR-HSA-997237 (Reactome)
SIN3AR-HSA-992696 (Reactome)
Single-stranded DNAR-HSA-983218 (Reactome)
Small Maf family membersR-HSA-1008240 (Reactome)
TP53 TetramerR-HSA-992696 (Reactome)
Type-I IFN genesR-HSA-994034 (Reactome)
VPS45R-HSA-1011600 (Reactome)
WEE1R-HSA-1013881 (Reactome)
ZFPM proteins:GATA proteinsArrowR-HSA-996755 (Reactome)
ZFPM1, ZFPM2R-HSA-996755 (Reactome)
ZFYVE20R-HSA-1011576 (Reactome)
ZFYVE20R-HSA-1011600 (Reactome)
adenosine 5'-monophosphateR-HSA-1008248 (Reactome)
f-actinR-HSA-994169 (Reactome)
p-Y813-JAK2R-HSA-997237 (Reactome)
p53:MYB:SIN3AArrowR-HSA-992696 (Reactome)
Personal tools