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

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13, 34, 3732, 365, 281, 21, 23, 26, 2716615124313024323325391819, 2010, 35111438811mitochondrial matrixcytosolnucleoplasmendosome lumenIRF2 ITPK1EHD1 DOCK11 IFNA6 gene IFNB1 gene MAFF RCOR1 HBG1 gene RAD51BPRKAR2B DOCK6 IFNA1 gene CABLES1 IFNA7 gene F-actin cappingproteinGATA1 IFNA8 gene HDAC2 DOCK-GEFs:RAC1,CDC42HBE1RCOR1 CDK5DOCK7 IRF1 CABLES1 AK3DOCK2 CAPZA2 DOCK8 DOCK11 CDK5:CABLES:ABLEHD1 ADPPromotor region ofbeta-globinPRKACA CBX5IFNA4 gene MFN2 CAPZA1 PHF21A RAD51B:RAD51C:Single-stranded DNALRRC16AKDM1A DOCK9 CAPZA2 SH2B3 PRKAR2A IFNA5 gene IFNA17 gene DOCK8 RCOR1 GATA6 NF-E2MitofusinsAKAP1 f-actin Type-I IFN genesCAPZBPromotor region of beta-globin CAPZA2 REST DNA binding sites HMG20B FAD p-Y813-JAK2ABL1 CAPZA1 ZFYVE20 F-actin cappingprotein:f-actinHDAC2 SH2Bfamily:p-Y813-JAK2Histone H3 HBG2I(3,4,5,6)P4MFN1 I(1,3,4,6)P4Rabenosyn-5:VPS-45RAC1, CDC42LRRC16A:F-actincapping proteinPRKAR2B RAB5AHBG2 gene C-terminalEHdomaincontainingproteins:Rabenosyn-5DOCK4 PKA tetramerSH2B2 IFNA14 gene Histone H3 methylated at lysine-9 IRF2IRF2:promoters ofINF alpha, INF betaIFNA8 gene PRKAR1A IFNA2 gene IFNB1 ZFPM1 Histone H3 mono- orunmethylated at K9GATA5 Histone H3 mono ordi-methylated at K9Globin genesNFE2 AKAP1 O2IFNA4 gene ATPZFPM2 MAFG CDK2:CABLES1:WEE1DOCK8 IFNA PRKACG DOCK10 ZFPM1, ZFPM2C-terminal EH domaincontaining proteinsIFNA10 gene DOCK1 PRKACA p-Y813-JAK2 DOCK4 CAPZB Histone H3 dimethylated at lysine-9 RAB5A KinesinsCABLES2 MAFG I(1,3,4,5)P4CAPZA1 GATA3 IFNB1 geneSingle-stranded DNA CAPZB CDK5 PHF21A Dual-specificAKAPs:PKA tetramerTP53 IFNA21 gene MAFK DOCK7 DOCK3 TP53 IFNA17 gene IFNB1 gene IFNA5 gene SH2B familyMYBDOCK5 KDM1A IFNA genesSH2B1 GTPCBX5 DOCK10 VPS45 PRKAR1B CDC42 AKAP10 MYB NADPHMitofusin complexJMJD1CREST:REST DNAbinding sitesIFNA1 gene CABLES1GATA3 MeK-H3F3A IFNA16 gene GATA2 IFNA7 gene CAPZA1 MAFF Small Maf familymembersZFPM1 p53:MYB:SIN3AIFNA10 gene NF-E2:Promoterregion ofbeta-globinIFN alpha/beta(IFNA/B)ZFPM proteins:GATAproteinsCAPZB IFNA14 gene HBE1 gene H2O2CDK2 MAFG CDK2NADP+IFNA21 gene GATA5 CDC42 ZFYVE20Dual-specific AKAPsPRKAR1B MeK-HIST2H3A DOCK2 HBD gene MAFK LRRC16A IFNA14 gene DOCK8 SH2B2 DOCK-GEFsF-actin cappingprotein alphasubunitNFE2BHC complexMeK10-HIST1H3A AKAP10 MeK-HIST2H3A GDPMFN2 MICAL1 GATA proteinsMAFK adenosine5'-monophosphateSingle-stranded DNAf-actinIFNB1 gene MAFF RAC1 IRF1ABL1IFNA2 gene CABLES1 WEE1DOCK9 ZFYVE20 IFNA10 gene GATA2 IFNA6 gene EHD3 IFNA1 gene SIN3A PRKACG HDAC1 MeK-H3F3A HDAC1 HBDHBG1DOCK6 CABLESI(1,3,4)P3IFNA8 gene ADPMICAL1:FADADPRAD51B:RAD51CCAPZA2 HP1alpha:Histone H3methylated at K9SH2B3 RAC1 VPS45SIN3AIFNA7 gene RAD51C IFNA17 gene EHD2 REST DNA binding sites EHD3 HBBPRKAR2A GATA1 SH2B1 PRKACB HMG20B I(1,3,4,5,6)P5GATA4 NFE2 WEE1 IFNA4 gene CABLES2 IFNA21 gene IFNA genes GATA4 MFN1 ATPDOCK1 IFNA6 gene RAD51B IFNA16 gene BHCcomplex:REST:RESTDNA binding sitesGATA6 HBB gene ZFPM2 Histone H3methylated atlysine-9IFNA5 gene EHD2 TP53 TetramerPRKAR1A RAD51CHistone H3 methylated at lysine-9 DOCK3 IRF1:Promotors ofIFN alpha, IFN betaDOCK5 IFNA2 gene RAD51B MeK10-HIST1H3A RAD51C IFNA16 gene PRKACB 177, 9, 22, 292


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: 66
Reactome Author 
Reactome Author: Akkerman, Jan Willem N

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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:16761 (ChEBI)
AK3ProteinQ9UIJ7 (Uniprot-TrEMBL)
AKAP1 ProteinQ92667 (Uniprot-TrEMBL)
AKAP10 ProteinO43572 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:15422 (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

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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)
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