SUMOylation is a regulator of the translocation of Jak2 between nucleus and cytosol.

Jak2 (Janus kinase 2) initiates the signal transduction of many cytokine receptors. We discovered that Jak2 is SUMOylated on multiple lysine residues by SUMO2/3 (small ubiquitin-related modifier 2/3) chains. Analysis of Jak2 mutants revealed that Jak2 SUMOylation depends on the presence of an active catalytic site. We used the GH (growth hormone) receptor to study the physiological relevance of Jak2 SUMOylation. Both GH stimulation and several other environmental stressors increased Jak2 SUMOylation. Cell fractionation showed that SUMOylated Jak2 is mainly present in the nucleus. The constitutively active V617F Jak2 mutant, implicated in myeloproliferative diseases, was highly SUMOylated in the absence of stimuli. These data provide evidence that Jak2 SUMOylation controls Jak2 shuttling between cytoplasm and nucleus.