Regulation of RUNX2 expression and activity (Homo sapiens)

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1, 4-8, 10...18, 2814, 16, 29, 30, 32261210, 2013, 2531252118, 28301618, 282925121612263, 1232162010, 17, 19, 20, 3113, 25, 2613, 253, 1265, 176cytosolnucleoplasmPSMD2 RUNX2-P2PSMB4 CUL1 UBC(153-228) STAT1 PolyUb-RUNX2-P2 PolyUb,p-S280,S284,S288-RUNX2-P2 PSMC5 ESRRA:PPARGC1AUBC(77-152) RUNX2-P2 SKP1 PSMD10 PSMF1 PPARGC1A PSMD2 SMURF1 gene DLX5,(DLX6)RUNX2 gene UBC(1-76) PSMB1 DLX6 UBC(305-380) PSMA8 RUNX2-P1 RUNX2-P2 GSK3B PPARGC1A UBC(533-608) PSMB2 PSMC6 PSMA1 PSMB8 PSMA5 DEXA GSK3B RPS27A(1-76) UBC(153-228) HIVEP3 UBC(153-228) MSX2:RUNX2 geneUBC(609-684) PSMB10 UBC(457-532) UBC(229-304) UBB(153-228) PSMB5 RUNX2-P1 UBC(457-532) FBXW7alpha:SKP1:CUL1:RBX1:PolyUb,p-3S-RUNX2:GSK3BRUNX2-P2 PSMB10 PSMD13 CUL1 RUNX2-P1:CBFBCBFB PSMD11 UBB(153-228) PSMD14 RUNX2-P2 ESRRA:PPARG1CB:RUNX2geneRUNX2 geneMSX2PolyUb-RUNX2-P2 GSK3B UBC(609-684) RPS27A(1-76) UBC(153-228) PSMA5 RUNX2-P1RUNX2-P2 RUNX2-P1 p-S280,S284,S288-RUNX2-P2 PSMD3 RUNX2 gene UbPolyUb-RUNX2-P2 RUNX2-P2 UBC(1-76) PSMD9 UBC(381-456) RUNX2:SMURF1RBX1 PSMB11 PSMD5 UBB(1-76) PSMD5 UBC(609-684) UBC(457-532) PSMC5 RBX1 PolyUb-RUNX2-P1 CUL1 RUNX2-P1 UBC(77-152) PSMD12 CUL1 PSMD11 RUNX2:GSK3BUBC(533-608) UBB(77-152) p-3S-RUNX2:GSK3BNR3C1 RUNX2-P1 UbUBB(77-152) RUNX2-P1 TWIST1:RUNX2 genePSMD7 PSMA6 RUNX2 gene PolyUb-RUNX2PPARGC1B GSK3B PolyUb-RUNX2:HIVEP3:WWP1ESRRA PSMD9 ESRRA:PPARGC1BUBC(1-76) PSMC6 PSMC4 PSMA4 RUNX2-P2 RUNX2-P2 PSMD6 SKP2 PSMB3 RBX1 RUNX2:CBFB:SMURF1genePSMD14 p-S294,S298,S302-RUNX2-P1 PSMA7 UBC(305-380) SKP1 RUNX2 gene RUNX2 gene PSMC2 PSMB1 PSMD1 PSME3 PSME1 PSMD6 UBB(1-76) DLX5,(DLX6):RUNX2geneESRRA p-S294,S298,S302-RUNX2-P1 ATPUBA52(1-76) NKX3-2UBC(533-608) ADPUBC(77-152) RBX1 UBC(381-456) PSMC4 PSMA3 RUNX2-P1 PSMD3 UBB(153-228) UBC(609-684) FBXW7alpha:SKP1:CUL1:RBX1:p-3S-RUNX2:GSK3BPSMA3 PSMC3 CBFB SMURF1PSME3 PSMB7 UBB(77-152) STUB1 ESR1:estrogen:RUNX2genePolyUb-RUNX2-P1 RBX1 RUNX2 gene ESRRA PSMD1 PSMA6 PSMC1 RUNX2 gene HIVEP3 PSMD8 UBB(1-76) SHFM1 PolyUb,p-S294,S298,S302-RUNX2-P1 UBC(457-532) PSMB6 CBFB RUNX2:CBFBBMP2 dimerPSMB6 DEXA PSMB9 26S proteasomeDLX5 NR3C1 PSMA2 SKP1 RUNX2-P1 UBC(229-304) FBXW7alpha RUNX2-P1 CBFB RUNX2UBC(381-456) ESR1 CBFB PSMA4 PSMC2 RUNX2:HIVEP3:WWP1RPS27A(1-76) UBC(305-380) PSMB7 PSMB3 UBB(153-228) PSMA1 ESRRA:PPARG1CA:RUNX2geneSKP1 UbUBA52(1-76) SKP1 UbPSMF1 RUNX2-P1 TWIST1FBXW7alpha ESTG RUNX2 gene PSMD13 GSK3BUBA52(1-76) SCF(SKP2) complexRUNX2-P2:CBFBRUNX2 gene PSMD4 UBB(1-76) RUNX2 gene RUNX2UBC(77-152) RUNX2-P1 CUL1 ESTG 26S proteasomeSTUB1PSMB9 ESRRA RUNX2-P2 RUNX2-P2:CBFB:RUNX2genePSMA2 RUNX2-P2 PSMB5 PSMC3 NR3C1:DexamethasoneRUNX2:STUB1PSMD8 STAT1RUNX2-P1 p-S280,S284,S288-RUNX2-P2 PolyUb-RUNX2-P1 PSME2 RUNX2:SCF(SKP2)SMURF1 geneWWP1 PSME4 PSME2 RUNX2-P1:CBFB:RUNX2genePSME1 UBC(381-456) ESR1:ESTGSKP2 NKX3-2:RUNX2 genePSMB8 WWP1BMP2 SHFM1 NKX3-2 UBB(77-152) RUNX2-P2 CBFB DEXA:NR3C1:RUNX2genePSMC1 RUNX2-P2 PolyUb-RUNX2RUNX2:STAT1UBA52(1-76) WWP1 UBC(229-304) PSMB2 UBC(229-304) DLX6 HIVEP3PSMD4 PPARGC1B UBC(305-380) MSX2 UBC(1-76) PSMD7 PSMD12 ESR1 FBXW7alpha:SKP1:CUL1:RBX1PSMB4 RPS27A(1-76) PSMD10 TWIST1 DLX5 SMURF1 UBC(533-608) PSMA7 FBXW7alpha 916211816298992322, 3499172010, 2034262, 15253422, 3427, 3327, 3316


Description

Several transcription factors have been implicated in regulation of the RUNX2 gene transcription. Similar to the RUNX1 gene, the RUNX2 gene expression can be regulated from the proximal P2 promoter or the distal P1 promoter (reviewed in Li and Xiao 2007).
Activated estrogen receptor alpha (ESR1) binds estrogen response elements (EREs) in the P2 promoter and stimulates RUNX2 transcription (Kammerer et al. 2013). Estrogen-related receptor alpha (ERRA) binds EREs or estrogen-related response elements (ERREs) in the P2 promoter of RUNX2. When ERRA is bound to its co-factor PPARG1CA (PGC1A), it stimulates RUNX2 transcription. When bound to its co-factor PPARG1CB (PGC1B), ERRA represses RUNX2 transcription (Kammerer et al. 2013).
TWIST1, a basic helix-loop-helix (bHLH) transcription factor, stimulates RUNX2 transcription by binding to the E1-box in the P2 promoter (Yang, Yang et al. 2011). TWIST proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004). Schnurri-3 (SHN3) is another protein that interacts with RUNX2 to decrease its availability in the nucleus and therefore its activity (Jones et al. 2006). In contrast, RUNX2 and SATB2 interact to enhance the expression of osteoblast-specific genes (Dobreva et al. 2006). Formation of the heterodimer with CBFB (CBF-beta) also enhances the transcriptional activity of RUNX2 (Kundu et al. 2002, Yoshida et al. 2002, Otto et al. 2002).
Transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012).
NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene and inhibits its transcription (Lengner et al. 2005). RUNX2-P1 transcription is also autoinhibited by RUNX2-P1, which binds to RUNX2 response elements in the P1 promoter of RUNX2 (Drissi et al. 2000). In contrast, binding of RUNX2-P2 to the proximal P2 promoter autoactivates transcription of RUNX2-P2 (Ducy et al. 1999). Binding of a homeodomain transcription factor DLX5, and possibly DLX6, to the RUNX2 P1 promoter stimulates RUNX2 transcription (Robledo et al. 2002, Lee et al. 2005). The homeobox transcription factor MSX2 can bind to DLX5 sites in the promoter of RUNX2 and inhibit transcription of RUNX2-P1 (Lee et al. 2005).
Translocation of RUNX2 protein to the nucleus is inhibited by binding to non-activated STAT1 (Kim et al. 2003).
Several E3 ubiquitin ligases were shown to polyubiquitinate RUNX2, targeting it for proteasome-mediated degradation: FBXW7a (Kumar et al. 2015), STUB1 (CHIP) (Li et al. 2008), SMURF1 (Zhao et al. 2003, Yang et al. 2014), WWP1 (Jones et al. 2006), and SKP2 (Thacker et al. 2016). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8939902
Reactome-version 
Reactome version: 62
Reactome Author 
Reactome Author: Orlic-Milacic, Marija

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101653view11:51, 1 November 2018ReactomeTeamreactome version 66
101189view21:39, 31 October 2018ReactomeTeamreactome version 65
100716view20:11, 31 October 2018ReactomeTeamreactome version 64
100266view16:57, 31 October 2018ReactomeTeamreactome version 63
99819view15:21, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99373view13:15, 31 October 2018DeSlOntology Term : 'regulatory pathway' added !
99372view12:48, 31 October 2018ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-177750 (Reactome)
26S proteasomeComplexR-HSA-68819 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
BMP2 ProteinP12643 (Uniprot-TrEMBL)
BMP2 dimerComplexR-HSA-201463 (Reactome)
CBFB ProteinQ13951 (Uniprot-TrEMBL)
CUL1 ProteinQ13616 (Uniprot-TrEMBL)
DEXA MetaboliteCHEBI:41879 (ChEBI)
DEXA:NR3C1:RUNX2 geneComplexR-HSA-9009086 (Reactome)
DLX5 ProteinP56178 (Uniprot-TrEMBL)
DLX5,(DLX6):RUNX2 geneComplexR-HSA-9007721 (Reactome)
DLX5,(DLX6)ComplexR-HSA-9007779 (Reactome)
DLX6 ProteinP56179 (Uniprot-TrEMBL)
ESR1 ProteinP03372 (Uniprot-TrEMBL)
ESR1:ESTGComplexR-HSA-1254381 (Reactome)
ESR1:estrogen:RUNX2 geneComplexR-HSA-8939910 (Reactome)
ESRRA ProteinP11474 (Uniprot-TrEMBL)
ESRRA:PPARG1CA:RUNX2 geneComplexR-HSA-8939930 (Reactome)
ESRRA:PPARG1CB:RUNX2 geneComplexR-HSA-8939943 (Reactome)
ESRRA:PPARGC1AComplexR-HSA-8939924 (Reactome)
ESRRA:PPARGC1BComplexR-HSA-8939923 (Reactome)
ESTG MetaboliteCHEBI:50114 (ChEBI)
FBXW7alpha ProteinQ969H0-1 (Uniprot-TrEMBL)
FBXW7alpha:SKP1:CUL1:RBX1:PolyUb,p-3S-RUNX2:GSK3BComplexR-HSA-9008665 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:p-3S-RUNX2:GSK3BComplexR-HSA-9008647 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1ComplexR-HSA-3215119 (Reactome)
GSK3B ProteinP49841 (Uniprot-TrEMBL)
GSK3BProteinP49841 (Uniprot-TrEMBL)
HIVEP3 ProteinQ5T1R4 (Uniprot-TrEMBL)
HIVEP3ProteinQ5T1R4 (Uniprot-TrEMBL)
MSX2 ProteinP35548 (Uniprot-TrEMBL)
MSX2:RUNX2 geneComplexR-HSA-9007758 (Reactome)
MSX2ProteinP35548 (Uniprot-TrEMBL)
NKX3-2 ProteinP78367 (Uniprot-TrEMBL)
NKX3-2:RUNX2 geneComplexR-HSA-8985291 (Reactome)
NKX3-2ProteinP78367 (Uniprot-TrEMBL)
NR3C1 ProteinP04150 (Uniprot-TrEMBL)
NR3C1:DexamethasoneComplexR-HSA-879850 (Reactome)
PPARGC1A ProteinQ9UBK2 (Uniprot-TrEMBL)
PPARGC1B ProteinQ86YN6 (Uniprot-TrEMBL)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
PolyUb,p-S280,S284,S288-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
PolyUb,p-S294,S298,S302-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
PolyUb-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
PolyUb-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
PolyUb-RUNX2:HIVEP3:WWP1ComplexR-HSA-9008103 (Reactome)
PolyUb-RUNX2ComplexR-HSA-9008097 (Reactome)
PolyUb-RUNX2ComplexR-HSA-9008122 (Reactome)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
RUNX2 gene ProteinENSG00000124813 (Ensembl)
RUNX2 geneGeneProductENSG00000124813 (Ensembl)
RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)
RUNX2-P1:CBFB:RUNX2 geneComplexR-HSA-9008361 (Reactome)
RUNX2-P1:CBFBComplexR-HSA-9016495 (Reactome)
RUNX2-P1ProteinQ13950-1 (Uniprot-TrEMBL)
RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
RUNX2-P2:CBFB:RUNX2 geneComplexR-HSA-9016527 (Reactome)
RUNX2-P2:CBFBComplexR-HSA-9016525 (Reactome)
RUNX2-P2ProteinQ13950-2 (Uniprot-TrEMBL)
RUNX2:CBFB:SMURF1 geneComplexR-HSA-9009447 (Reactome)
RUNX2:CBFBComplexR-HSA-8865420 (Reactome)
RUNX2:GSK3BComplexR-HSA-9008489 (Reactome)
RUNX2:HIVEP3:WWP1ComplexR-HSA-9008033 (Reactome)
RUNX2:SCF(SKP2)ComplexR-HSA-8939702 (Reactome)
RUNX2:SMURF1ComplexR-HSA-9009416 (Reactome)
RUNX2:STAT1ComplexR-HSA-9008005 (Reactome)
RUNX2:STUB1ComplexR-HSA-9009311 (Reactome)
RUNX2ComplexR-HSA-9007751 (Reactome)
RUNX2ComplexR-HSA-9007986 (Reactome)
SCF(SKP2) complexComplexR-HSA-8939693 (Reactome)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SKP1 ProteinP63208 (Uniprot-TrEMBL)
SKP2 ProteinQ13309 (Uniprot-TrEMBL)
SMURF1 ProteinQ9HCE7 (Uniprot-TrEMBL)
SMURF1 gene ProteinENSG00000198742 (Ensembl)
SMURF1 geneGeneProductENSG00000198742 (Ensembl)
SMURF1ProteinQ9HCE7 (Uniprot-TrEMBL)
STAT1 ProteinP42224 (Uniprot-TrEMBL)
STAT1ProteinP42224 (Uniprot-TrEMBL)
STUB1 ProteinQ9UNE7 (Uniprot-TrEMBL)
STUB1ProteinQ9UNE7 (Uniprot-TrEMBL)
TWIST1 ProteinQ15672 (Uniprot-TrEMBL)
TWIST1:RUNX2 geneComplexR-HSA-8940046 (Reactome)
TWIST1ProteinQ15672 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
UbComplexR-HSA-6782667 (Reactome)
WWP1 ProteinQ9H0M0 (Uniprot-TrEMBL)
WWP1ProteinQ9H0M0 (Uniprot-TrEMBL)
p-3S-RUNX2:GSK3BComplexR-HSA-9008635 (Reactome)
p-S280,S284,S288-RUNX2-P2 ProteinQ13950-2 (Uniprot-TrEMBL)
p-S294,S298,S302-RUNX2-P1 ProteinQ13950-1 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-8939801 (Reactome)
26S proteasomemim-catalysisR-HSA-9008110 (Reactome)
26S proteasomemim-catalysisR-HSA-9008475 (Reactome)
26S proteasomemim-catalysisR-HSA-9009362 (Reactome)
ADPArrowR-HSA-9008480 (Reactome)
ATPR-HSA-9008480 (Reactome)
BMP2 dimerArrowR-HSA-9007707 (Reactome)
DEXA:NR3C1:RUNX2 geneArrowR-HSA-9009085 (Reactome)
DEXA:NR3C1:RUNX2 geneTBarR-HSA-8939900 (Reactome)
DLX5,(DLX6):RUNX2 geneArrowR-HSA-9007686 (Reactome)
DLX5,(DLX6):RUNX2 geneArrowR-HSA-9007707 (Reactome)
DLX5,(DLX6)R-HSA-9007707 (Reactome)
ESR1:ESTGR-HSA-8939904 (Reactome)
ESR1:estrogen:RUNX2 geneArrowR-HSA-8939900 (Reactome)
ESR1:estrogen:RUNX2 geneArrowR-HSA-8939904 (Reactome)
ESRRA:PPARG1CA:RUNX2 geneArrowR-HSA-8939900 (Reactome)
ESRRA:PPARG1CA:RUNX2 geneArrowR-HSA-8939929 (Reactome)
ESRRA:PPARG1CB:RUNX2 geneArrowR-HSA-8939938 (Reactome)
ESRRA:PPARG1CB:RUNX2 geneTBarR-HSA-8939900 (Reactome)
ESRRA:PPARGC1AR-HSA-8939929 (Reactome)
ESRRA:PPARGC1BR-HSA-8939938 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:PolyUb,p-3S-RUNX2:GSK3BArrowR-HSA-9008479 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:PolyUb,p-3S-RUNX2:GSK3BR-HSA-9008475 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:p-3S-RUNX2:GSK3BArrowR-HSA-9008478 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:p-3S-RUNX2:GSK3BR-HSA-9008479 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1:p-3S-RUNX2:GSK3Bmim-catalysisR-HSA-9008479 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1ArrowR-HSA-9008475 (Reactome)
FBXW7alpha:SKP1:CUL1:RBX1R-HSA-9008478 (Reactome)
GSK3BArrowR-HSA-9008475 (Reactome)
GSK3BR-HSA-9008476 (Reactome)
HIVEP3ArrowR-HSA-9008110 (Reactome)
HIVEP3R-HSA-9008036 (Reactome)
MSX2:RUNX2 geneArrowR-HSA-9007759 (Reactome)
MSX2:RUNX2 geneTBarR-HSA-9007686 (Reactome)
MSX2R-HSA-9007759 (Reactome)
NKX3-2:RUNX2 geneArrowR-HSA-8985293 (Reactome)
NKX3-2:RUNX2 geneTBarR-HSA-9007686 (Reactome)
NKX3-2R-HSA-8985293 (Reactome)
NR3C1:DexamethasoneR-HSA-9009085 (Reactome)
PolyUb-RUNX2:HIVEP3:WWP1ArrowR-HSA-9008076 (Reactome)
PolyUb-RUNX2:HIVEP3:WWP1R-HSA-9008110 (Reactome)
PolyUb-RUNX2ArrowR-HSA-8939706 (Reactome)
PolyUb-RUNX2ArrowR-HSA-9009308 (Reactome)
PolyUb-RUNX2ArrowR-HSA-9009403 (Reactome)
PolyUb-RUNX2R-HSA-8939801 (Reactome)
PolyUb-RUNX2R-HSA-9009362 (Reactome)
R-HSA-8939688 (Reactome) The E3 ubiquitin ligase complex SCF binds RUNX2 through direct interaction between SKP2 subunit of the SCF complex and RUNX2 (Thacker et al. 2016). This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015).
R-HSA-8939706 (Reactome) The SCF(SKP2) E3 ubiquitin ligase complex polyubiquitinates RUNX2 on unknown lysine residues, targeting it for proteasome-mediated degradation. SKP2-triggered RUNX2 degradation negatively regulates osteogenesis by inhibiting differentiation of osteoblasts (Thacker et al. 2016). This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015).
R-HSA-8939801 (Reactome) Polyubiquitinated RUNX2 is degraded by the proteasome. As it has not been examined whether SCF(SKP2)-mediated polyubiquitination of RUNX2 leads to translocation of PolyUb-RUNX2 to the cytosol (Thacker et al. 2016), proteasome mediated degradation is assumed to happen in the nucleus. This process is inhibited by glucose uptake in osteoblasts (Wei et al. 2015).
R-HSA-8939900 (Reactome) Activated estrogen receptor alpha (ESR1) directly stimulates the RUNX2 gene transcription by binding to estrogen response elements in the proximal P2 promoter of RUNX2. Estrogen-related receptor alpha (ESRRA) binds to estrogen response elements (EREs) or estrogen-related response elements (ERREs) in the proximal P2 promoter of the RUNX2 gene. In the presence of its PPARG1CA co-factor, ESRRA stimulates RUNX2 transcription. In the presence of another co-factor, PPARG1CB, ESRRA inhibits RUNX2 transcription (Kammerer et al. 2013).
Transcription of RUNX2 is stimulated by binding of TWIST1 transcription factor to the E1-box in the proximal P2 promoter of RUNX2 (Yang et al. 2011).
Studies in mice have shown that RUNX2-P2 can autoactivate its own expression by binding to the proximal P2 promoter of the RUNX2 gene (Ducy et al. 1999).

Based on studies in mice, transcription of RUNX2 from the proximal promoter is inhibited by binding of the glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) to a glucocorticoid receptor response element (GRE), which is also present in the human promoter (Zhang et al. 2012). The complex of DEXA and NR3C1 may also inhibit RUNX2 activity by directly binding to the RUNX2 protein (Koromila et al. 2013).

R-HSA-8939904 (Reactome) Activated estrogen receptor alpha (ESR1) binds estrogen response elements in the proximal P2 promoter of the RUNX2 gene (Kammerer et al. 2013).
R-HSA-8939929 (Reactome) Estrogen-related receptor alpha (ESRRA), in complex with its co-activator PPARG1CA (PGC1A), binds estrogen response elements (EREs) and/or estrogen-related response elements (ERREs) in the proximal P2 promoter of the RUNX2 gene (Kammerer et al. 2013).
R-HSA-8939938 (Reactome) Estrogen-related receptor alpha (ESRRA), in complex with its co-activator PPARG1CB (PGC1B), binds estrogen response elements (EREs) and/or estrogen-related response elements (ERREs) in the proximal P2 promoter of the RUNX2 gene (Kammerer et al. 2013).
R-HSA-8940032 (Reactome) TWIST1 transcription factor binds the proximal P2 promoter of RUNX2. Binding involves the basic helix-loop-helix (bHLH) domain of TWIST1 and E1-box in the P2 promoter of RUNX2 (Yang et al. 2011). TWIST1, a transcriptional target of HIF1A (Yang et al. 2008) and STAT3 (Zhang et al. 2015), induces epithelial-to-mesenchymal transition (EMT) and promotes cancer metastasis (Yang et al. 2004). In zebrafish, Twist-mediated transactivation of runx2 controls skeletal development and dorsoventral patterning (Yang et al. 2011). Twist proteins also interact with the DNA-binding domain of RUNX2 to modulate its activity during skeletogenesis (Bialek et al. 2004).
R-HSA-8985293 (Reactome) Based on studies in mice, the homeobox protein NKX3-2 (BAPX1), required for embryonic development of the axial skeleton (Tribioli and Lufkin 1999), binds the distal (P1) promoter of the RUNX2 gene (Lengner et al. 2005). NKX3-2 binding sites are conserved in the human RUNX2 promoter.
R-HSA-9007686 (Reactome) Based on studies in mice, RUNX2 transcription is repressed by binding of the transcriptional repressor NKX3-2 (BAPX1) to the distal (P1) RUNX2 gene promoter (Lengner et al. 2005, Provot et al. 2006). RUNX2 itself can autoregulate through a negative feedback mechanism by binding of the RUNX2-P1 isoform to the evolutionarily conserved RUNX2 response elements in the distal P1 promoter (Drissi et al. 2000).

Based on studies in mice, transcription of RUNX2 from the distal (P1) promoter is directly stimulated by DLX5 (and possibly DLX6). Binding of DLX5 to the RUNX2 promoter is antagonized by MSX2. Once bound to the RUNX2 promoter, MSX2 inhibits RUNX2 transcription (Lee et al. 2005). DLX5 is activated by BMP2 signaling through an unknown mechanism.
Transcription of RUNX2 from the P1 promoter may be inhibited by the transcriptional repressor GFI1, which is essential for hematopoiesis (D'Souza et al. 2011).

R-HSA-9007707 (Reactome) Based on studies in mice, in response to BMP2 signaling, a homeodomain transcription factor DLX5 binds to three sites in the distal (P1) promoter of the RUNX2 gene (Lee et al. 2005). DLX5 binding sites are conserved in the human RUNX2 promoter.

Dlx5 deficient mice show a mild delay in ossification of long bones and close to normal Runx2 expression. Mice that are double knockouts for Dlx5 and Dlx6 genes show severe defects in the formation of limbs, cranium and axial skeleton and die after birth. Dlx5/6 double knockouts show reduction in the number of Runx2-expressing chondrocytes (Robledo et al. 2002). As DLX6 is suggested by several studies to be redundant with DLX5 in the regulation of RUNX2 expression (Robledo et al. 2002, Holleville et al. 2007, Barron et al. 2011), although direct binding of DLX6 to the RUNX2 gene promoter has not been tested, DLX6 is shown as a candidate transcriptional regulator of RUNX2.

R-HSA-9007759 (Reactome) Based on studies in mice, homeobox transcription factor MSX2 binds to DLX5 sites in the distal (P1) promoter of the RUNX2 gene, which are conserved between mice and humans, and antagonizes DLX5 binding (Lee et al. 2005).
R-HSA-9007999 (Reactome) Based on studies in mice, binding of RUNX2 to cytosolic STAT1 inhibits RUNX2 translocation to the nucleus (Kim et al. 2003).
R-HSA-9008015 (Reactome) Based on studies in mice, RUNX2 forms a complex with non-active (unphosphorylated) STAT1 in the cytosol. The interaction between the two proteins involves the DNA binding and linker domain of STAT1 and the Runt domain of RUNX2. Binding to STAT1 prevents translocation of RUNX2 to the nucleus and thus interferes with activation of RUNX2 target genes. STAT1 phosphorylation diminishes its interaction with RUNX2. Stat1 knockout mice exhibit increased bone mass and accelerated osteoblast differentiation, accompanied by enhnanced Runx2 activity (Kim et al. 2003).
R-HSA-9008036 (Reactome) Based on studies in mice, HIVEP3 (also known as SHN3 or Schnurri-3), a zinc finger adapter protein, binds to RUNX2 together with the E3 ubiquitin ligase WWP1. Hivep3 knockout mice exhibit increased bone mass, due to increased bone formation by osteoblasts, which is accompanied by increased expression of Runx2 target genes (Jones et al. 2006).
R-HSA-9008076 (Reactome) Studies in mice have shown that once HIVEP3 (SHN3, Schnurri-3) and WWP1 are bound to RUNX2, WWP1, an E3 ubiquitin ligase, polyubiquitinates RUNX2, targeting it for proteasome-mediated degradation. HIVEP3 overexpression in human embryonic kidney 293T cells leads to a dose-dependent decrease in RUNX2 protein levels (Jones et al. 2006).
R-HSA-9008110 (Reactome) Based on studies in mice, proteasome degrades RUNX2 polyubiquitinated by WWP1 in the context of the complex of RUNX2, HIVEP3 (SHN3, Schnurri-3) and WWP1 (Jones et al. 2006).
R-HSA-9008345 (Reactome) Based on studies in mice, RUNX2-P1 (RUNX2 variant expressed from the distal promoter) binds to RUNX2 response elements in the distal promoter of the RUNX2 gene, which are conserved in rat and human RUNX2 promoters (Drissi et al. 2000). It is assumed that RUNX2 is associated with at least CBFB and the RUNX2 promoter, although this has not been examined.
R-HSA-9008475 (Reactome) RUNX2, polyubiquitinated by FBXW7alpha in a GSK3B-dependant manner, is degraded by the proteasome (Kumar et al. 2015).
R-HSA-9008476 (Reactome) RUNX2 forms a complex with a serine/threonine kinase GSK3B. Since GSK3B can localize to both cytosol and nucleus, this reaction is shown to occur in the nucleoplasm, although this has not been experimentally tested (Kugimiya et al. 2007, Kumar et al. 2015).
R-HSA-9008478 (Reactome) FBXW7alpha, a component of an SCF ubiquitin ligase complex, binds to RUNX2 in the presence of GSK3B, probably after GSK3B phosphorylates RUNX2 (Kumar et al. 2015). The presence of other SCF complex components, besides FBXW7alpha, is assumed, although it has not been tested whether they co-immunoprecipitate with RUNX2 and GSK3B.
R-HSA-9008479 (Reactome) The E3 ubiquitin ligase FBXW7alpha, a component of an SCF ubiquitin ligase complex, polyubiquitinates RUNX2, targeting it for degradation. The presence of GSK3B, and probably prior phosphorylation of RUNX2 by GSK3B, is required for FBXW7alpha-mediated polyubiquitination of RUNX2 (Kumar et al. 2015).
R-HSA-9008480 (Reactome) GSK3B phosphorylates RUNX2 on three serine residues in an evolutionarily conserved motif SPPWSYDQS, which decreases the DNA binding ability of RUNX2 (Kugimiya et al. 2007, Kumar et al. 2015).
R-HSA-9009085 (Reactome) Based on studies in mice, glucocorticoid receptor (NR3C1) activated by dexamethasone (DEXA) binds to glucocorticoid receptor response element (GRE) in the proximal (P2) promoter of the RUNX2 gene. NR3C1 may also recruit histone deacetylase HDAC1 to the RUNX2 promoter (Zhang et al. 2012). Similar to the mouse promoter, human RUNX2 P2 promoter also contains GREs.
R-HSA-9009308 (Reactome) STUB1 (CHIP), an E3 ubiquitin ligase, promotes polyubiquitination of RUNX2, targeting it for proteasome-mediated degradation (Li et al. 2008).
R-HSA-9009309 (Reactome) RUNX2 binds to STUB1 (CHIP), an E3 ubiquitin ligase (Li et al. 2008).
R-HSA-9009362 (Reactome) RUNX2 polyubiquitinated by STUB1 (CHIP) (Li et al. 2008) or SMURF1 (Zhao et al. 2003, Yang et al. 2014) is degraded by the proteasome.
R-HSA-9009401 (Reactome) SMURF1, an E3 ubiquitin ligase, binds to RUNX2 (Zhao et al. 2003). While the direct interaction was demonstrated in mouse cells, it was shown that in human cells RUNX2 stability is increased upon SMURF1 knockdown while RUNX2 ubiquitination is decreased (Yang et al. 2014).
R-HSA-9009403 (Reactome) Based on studies in mice, SMURF1 polyubiquitinates RUNX2, targeting it for degradation (Zhao et al. 2003). In human cells, RUNX2 ubiquitination is decreased upon SMURF1 knockdown (Yang et al. 2014).
R-HSA-9009451 (Reactome) RUNX2, presumably in complex with CBFB, binds RUNX2 binding elements in the promoter of the SMURF1 gene, encoding an E3 ubiquitin ligase SMURF1 (Yang et al. 2014).
R-HSA-9009452 (Reactome) Binding of RUNX2, presumably in complex with CBFB, to the SMURF1 gene promoter stimulates SMURF1 transcription. As SMURF1 is an E3 ubiquitin ligase which targets RUNX2 for degradation, this creates a negative feedback loop (Yang et al. 2014).
R-HSA-9016526 (Reactome) Based on studies in mice, RUNX2-P2 (RUNX2 variant expressed from the proximal promoter) binds to RUNX2 response elements in the proximal P2 promoter of the RUNX2 gene (Ducy et al. 1999). It is assumed that RUNX2 is associated with at least CBFB and the RUNX2 promoter, although this has not been examined.
RUNX2 geneR-HSA-8939900 (Reactome)
RUNX2 geneR-HSA-8939904 (Reactome)
RUNX2 geneR-HSA-8939929 (Reactome)
RUNX2 geneR-HSA-8939938 (Reactome)
RUNX2 geneR-HSA-8940032 (Reactome)
RUNX2 geneR-HSA-8985293 (Reactome)
RUNX2 geneR-HSA-9007686 (Reactome)
RUNX2 geneR-HSA-9007707 (Reactome)
RUNX2 geneR-HSA-9007759 (Reactome)
RUNX2 geneR-HSA-9008345 (Reactome)
RUNX2 geneR-HSA-9009085 (Reactome)
RUNX2 geneR-HSA-9016526 (Reactome)
RUNX2-P1:CBFB:RUNX2 geneArrowR-HSA-9008345 (Reactome)
RUNX2-P1:CBFB:RUNX2 geneTBarR-HSA-9007686 (Reactome)
RUNX2-P1:CBFBR-HSA-9008345 (Reactome)
RUNX2-P1ArrowR-HSA-9007686 (Reactome)
RUNX2-P2:CBFB:RUNX2 geneArrowR-HSA-8939900 (Reactome)
RUNX2-P2:CBFB:RUNX2 geneArrowR-HSA-9016526 (Reactome)
RUNX2-P2:CBFBR-HSA-9016526 (Reactome)
RUNX2-P2ArrowR-HSA-8939900 (Reactome)
RUNX2:CBFB:SMURF1 geneArrowR-HSA-9009451 (Reactome)
RUNX2:CBFB:SMURF1 geneArrowR-HSA-9009452 (Reactome)
RUNX2:CBFBR-HSA-9009451 (Reactome)
RUNX2:GSK3BArrowR-HSA-9008476 (Reactome)
RUNX2:GSK3BR-HSA-9008480 (Reactome)
RUNX2:GSK3Bmim-catalysisR-HSA-9008480 (Reactome)
RUNX2:HIVEP3:WWP1ArrowR-HSA-9008036 (Reactome)
RUNX2:HIVEP3:WWP1R-HSA-9008076 (Reactome)
RUNX2:HIVEP3:WWP1mim-catalysisR-HSA-9008076 (Reactome)
RUNX2:SCF(SKP2)ArrowR-HSA-8939688 (Reactome)
RUNX2:SCF(SKP2)R-HSA-8939706 (Reactome)
RUNX2:SCF(SKP2)mim-catalysisR-HSA-8939706 (Reactome)
RUNX2:SMURF1ArrowR-HSA-9009401 (Reactome)
RUNX2:SMURF1R-HSA-9009403 (Reactome)
RUNX2:SMURF1mim-catalysisR-HSA-9009403 (Reactome)
RUNX2:STAT1ArrowR-HSA-9008015 (Reactome)
RUNX2:STAT1TBarR-HSA-9007999 (Reactome)
RUNX2:STUB1ArrowR-HSA-9009309 (Reactome)
RUNX2:STUB1R-HSA-9009308 (Reactome)
RUNX2:STUB1mim-catalysisR-HSA-9009308 (Reactome)
RUNX2ArrowR-HSA-9007999 (Reactome)
RUNX2R-HSA-8939688 (Reactome)
RUNX2R-HSA-9007999 (Reactome)
RUNX2R-HSA-9008015 (Reactome)
RUNX2R-HSA-9008036 (Reactome)
RUNX2R-HSA-9008476 (Reactome)
RUNX2R-HSA-9009309 (Reactome)
RUNX2R-HSA-9009401 (Reactome)
SCF(SKP2) complexArrowR-HSA-8939706 (Reactome)
SCF(SKP2) complexR-HSA-8939688 (Reactome)
SMURF1 geneR-HSA-9009451 (Reactome)
SMURF1 geneR-HSA-9009452 (Reactome)
SMURF1ArrowR-HSA-9009403 (Reactome)
SMURF1ArrowR-HSA-9009452 (Reactome)
SMURF1R-HSA-9009401 (Reactome)
STAT1R-HSA-9008015 (Reactome)
STUB1ArrowR-HSA-9009308 (Reactome)
STUB1R-HSA-9009309 (Reactome)
TWIST1:RUNX2 geneArrowR-HSA-8939900 (Reactome)
TWIST1:RUNX2 geneArrowR-HSA-8940032 (Reactome)
TWIST1R-HSA-8940032 (Reactome)
UbArrowR-HSA-8939801 (Reactome)
UbArrowR-HSA-9008110 (Reactome)
UbArrowR-HSA-9008475 (Reactome)
UbArrowR-HSA-9009362 (Reactome)
UbR-HSA-8939706 (Reactome)
UbR-HSA-9008076 (Reactome)
UbR-HSA-9008479 (Reactome)
UbR-HSA-9009308 (Reactome)
UbR-HSA-9009403 (Reactome)
WWP1ArrowR-HSA-9008110 (Reactome)
WWP1R-HSA-9008036 (Reactome)
p-3S-RUNX2:GSK3BArrowR-HSA-9008480 (Reactome)
p-3S-RUNX2:GSK3BR-HSA-9008478 (Reactome)
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