p(Y449)-IL7RA mediates STAT5 activation Authored: Ray, KP, 2010-05-17 Edited: Jupe, S, 2011-05-06 Multiple observations support a role for IL7-stimulated JAK/STAT signaling. IL7 induces rapid and dose-dependent tyrosine phosphorylation of JAKs 1 and 3, with concomitant tyrosine phosphorylation and DNA-binding activity of STAT5a/b (Foxwell et al. 1995). IL7RA was shown to directly induce the activation of JAKs and STATs 1, 5, and 3 by van der Plas et al. (1996). In primary human T cells and NK cells, IL7 induced activation of STAT5a, STAT5b and to a lesser extent STAT1 and STAT3 (Yu et al. 1998). Jak1 and Jak3 knockout mice displayed severely impaired thymic development, further supporting their importance in IL7 signaling (Rodig et al. 1998, Nosaka et al. 1995).<br><br> In human thymocytes, IL7 activates STAT5. It is thought that phosphorylated Y449 in the cytoplasmic domain of the IL7RA is a docking site for STAT5 (Pallard et al. 1999). STAT5 can be activated in COS 7 cells when co transfected with JAK3 (Lin et al. 1996), though this does not demonstrate that JAK3 phosphorylates STAT5 proteins in response to IL7 in vivo (Lin & Leonard, 2000); it is not clear which JAK kinase phosphorylates STAT5 in vivo. T-cells from an IL7RA Y449F knock-in mouse did not activate STAT5 (Osbourne et al. 2007), indicating that Tyr449 is a key residue regulating IL7 mediated STAT5 activation. STAT3 is critical for early B cell differentiation, but the details of its involvement are unclear (Chou et al 2006). Pubmed10367898 Pubmed10851055 Pubmed16825489 Pubmed17325202 Pubmed7481769 Pubmed7489741 Pubmed8631883 Pubmed8709637 Pubmed9590172 Pubmed9715265 Reactome Database ID Release 431295540 Reactome, http://www.reactome.org ReactomeREACT_115766 Reviewed: Puck, J, 2011-11-03 has a Stoichiometric coefficient of 2 STAT5 p-STAT5