Negative regulation of Jak2 by its auto-phosphorylation at tyrosine 913 via the Epo signaling pathway.
Janus kinase 2 (Jak2) has a pivotal role in erythropoietin (Epo) signaling pathway, including erythrocyte differentiation and Stat5 activation. In the course of screening for critical phosphorylation of tyrosine residues in Jak2, we identified tyrosine 913 (Y(913)) as a novel and functional phosphorylation site, which negatively regulates Jak2. Phosphorylation at Y(913) rapidly occurred and was sustained for at least 120 min after Epo stimulation, in contrast to the transient phosphorylation of Y(1007/1008) in the activation loop of Jak2. Interestingly, phosphorylation defective mutation of Y(913) (Y(913)F) results in a significant enhancement of Epo-induced Jak2 activation, whereas phosphorylation mimic mutation of Y(913) (Y(913)E) completely abrogated its activation. Furthermore, Jak2 deficient fetal liver cells expressing Y(913)F mutant generated many mature erythroid BFU-E and CFU-E colonies, while Y(913)E mutant failed to reconstitute Jak2 deficiency. We also demonstrate, in Jak1, phosphorylation of Y(939), a corresponding tyrosine residue with Y(913), negatively regulated Jak1 signaling pathway. Accordingly, our results suggest that this tyrosine phosphorylation in JH1 domain may be involved in common negative regulation mechanism for Jak family.
Funakoshi-Tago
Megumi
M
Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
Tago
Kenji
K
Kasahara
Tadashi
T
Parganas
Evan
E
Ihle
James N
JN
D000818:Animals; D003114:Colony-Forming Units Assay; D017124:Conserved Sequence; D004789:Enzyme Activation / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D004921:Erythropoietin; D019000:Phosphotyrosine; D007371:Interferon-gamma; D053614:Janus Kinase 2