TYROSINE RESIDUES WITHIN THE INTRACELLULAR DOMAIN OF THE ERYTHROPOIETIN RECEPTOR MEDIATE ACTIVATION OF AP-1 TRANSCRIPTION FACTORS

Binding of erythropoietin (Epo) to the Epo receptor (EpoR) initiates a signaling cascade resulting in tyrosine phosphorylation of several pr oteins and induction of AP-1 transcription factor(s). While Epo is kno wn to activate c-fos gene expression, the mechanism of AP-1 activation is unknown. Here we show that AP-1 activation by Epo requires tyrosin e kinase activity and also de novo protein synthesis. Using a mutant E poR containing no cytosolic tyrosine residues, and a set of eight muta nts containing a single cytosolic tyrosine residue, we show that multi ple EpoR tyrosines, thought to activate multiple intracellular signal transduction proteins, can mediate AP-1 activation. An EpoR containing only tyrosine 343 or tyrosine 464 supports a maximal level of AP-1 ac tivation We also show that AP-1 activation does not require maximal ST AT5 activation and may occur via a STAT5-independent signaling pathway .