Erythropoietin receptor-mediated Egr-1 activation: structural requirements and functional implications.
The transcription factor Egr-1 is encoded by an immediate early response gene and has been shown to be a key regulator in the induction of apoptosis, mitogenesis and differentiation. It is rapidly induced by different stimuli including the glycoprotein hormone erythropoietin. In this report, we analyse the role of different erythropoietin receptor substructures for the activation of Egr-1 and the functional consequences of Egr-1 overexpression in the erythroleukemic cell line ELM-I-1. The investigation of receptor variants revealed that the activity of JAK2 and the phosphorylation of receptor tyrosine residues are essential preconditions for the ability to target Egr-1. Furthermore, we observed a close correlation of the abilities of receptors to activate the Ras-MAPK pathway and Egr-1. Using mass spectrometry we identified the Ras-GTPase-activating protein-SH3-domain-binding protein 1 (G3BP-1), a component of the Ras network of proteins, as an Egr-1 interacting protein in EPO stimulated ELM-I-1 cells. The overexpression of Egr-1 in these cells resulted in an enhanced rate of spontaneous erythroid differentiation.
Schulze
Christoph
C
Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Schillingallee 70, PF100888, 18057 Rostock, Germany.
Büchse
Tom
T
Mikkat
Stefan
S
Bittorf
Thomas
T
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000737:chemistry* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007377:Interleukin-3 / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017467:Receptors, Erythropoietin / Q000737:chemistry* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D051766:Early Growth Response Protein 1; D020690:GTPase-Activating Proteins; D007377:Interleukin-3; D050505:Mutant Proteins; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D050791:STAT Transcription Factors; D019000:Phosphotyrosine; D004247:DNA; D066246:ErbB Receptors; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases