ETV3 affect on CSF1-promoted macrophage differentiation
CSF1 is involved in proliferation, differentiation and survival of cells of the monocyte/ macrophage lineage.
CSF1 acts via M-CSF receptor and transmits a growth and differentiation signal by activation of RAS signaling pathway , . Activated by CSF1 M-CSF receptor binds to GRB2 coupled with SOS1. Activated SOS1 stimulates H-Ras and it leads to ERK1/2 activation through H-Ras/ c-Raf-1/ MEK1(MAP2K1), MEK2(MAP2K2) pathway , . Activated ERK1/2 phosphorylates ETS1 and ETS2 , . Also, ERK1/2 activation by CSF1 leads to Elk-1 phosphorylation, Elk-1 binds to SRF and stimulates c-Fos transcription , , , . In addition, CSF1 stimulation enhances expression of ETS2 and c-Jun , . ETS1, ETS2, c-Jun and c-Fos forms ternary complexes and bind to composite ETS/AP-1 sites in PLAU (UPA) ,  and 08p22/MSR1(CD204) ,  promoters and thus promote macrophage differentiation , .
Proliferation signaling of CSF1 also involves RAS pathway and leads to ETS2 phosphorylation by ERK1/2. ETS2 binds to monomeric sites in c-Myc, CDK1 (p34) and PRIM2A promoters and thus promoter CSF1 induced proliferation , .
ETV3 of the ETS-domain family transcription factors that functions as a transcriptional repressor can block mitogenic responses mediated by positively acting Ets factors. ETV3 itself is induced by CSF1, most likely via CSF1 promoted p38 MAPK activation pathway during macrophage differentiation . p38 MAPK stimulates phosphorylation of CREM (activators) and CREB1, probably via MSK1/2 (RPS6KA5/4) . CREM (activators) and CREB1 in turn, activate transcription of ETV3 . Repressor activity of ETV3 is stimulated by binding of DDX20 associated with HDAC2, HDAC5, N-CoR, SMRT and Sin3A . ETV3 can bind only to monomeric ETS sites in PRIM2A, CDK1 (p34) and c-Myc promoters. Thus, it replaces ETS2 and represses promoter activity of proliferative genes. However, it is not able to bind to ETS/AP-1 composite sites, so promoters of differentiation-responsive genes remain unaffected by ETV3 and CSF1-induced cell differentiation goes on and cell proliferation is blocked .
| 08p22/MSR1(CD204) || Macrophage scavenger receptor types I and II |
| CDK1 (p34) || Cyclin-dependent kinase 1 |
| CREB1 || Cyclic AMP-responsive element-binding protein 1 |
| CREM (activators) || cAMP-responsive element modulator |
| CSF1 || Macrophage colony-stimulating factor 1 |
| DDX20 || Probable ATP-dependent RNA helicase DDX20 |
| ERK1/2 || Erk 1/2 Protein group |
| ETS1 || Protein C-ets-1 |
| ETS2 || Protein C-ets-2 |
| ETV3 || ETS translocation variant 3 |
| Elk-1 || ETS domain-containing protein Elk-1 |
| GRB2 || Growth factor receptor-bound protein 2 |
| H-Ras || GTPase HRas |
| HDAC2 || Histone deacetylase 2 |
| HDAC5 || Histone deacetylase 5 |
| M-CSF receptor || Macrophage colony-stimulating factor 1 receptor |
| MEK1(MAP2K1) || Dual specificity mitogen-activated protein kinase kinase 1 |
| MEK2(MAP2K2) || Dual specificity mitogen-activated protein kinase kinase 2 |
| MSK1/2 (RPS6KA5/4) || MSK1/2(RPS6KA5/4) |
| N-CoR || Nuclear receptor corepressor 1 |
| PLAU (UPA) || Urokinase-type plasminogen activator |
| PRIM2A || DNA primase large subunit |
| SMRT || Nuclear receptor corepressor 2 |
| SOS1 || Son of sevenless homolog 1 |
| SRF || Serum response factor |
| Sin3A || Paired amphipathic helix protein Sin3a |
| c-Fos || Proto-oncogene c-Fos |
| c-Jun || Transcription factor AP-1 |
| c-Myc || Myc proto-oncogene protein |
| c-Raf-1 || RAF proto-oncogene serine/threonine-protein kinase |
| p38 MAPK || p38 mitogen-activated protein kinase Protein group |
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