Roles of Jak2 in leptin action: From molecular signaling to physiology.

摘要

The adipose-derived hormone leptin regulates energy and glucose homeostasis. The signaling form of the leptin receptor, LepRb, constitutively associates with Jak2, which is activated upon ligand binding, phosphorylating several tyrosine residues on itself and on the intracellular tail of LepRb. Jak2 is essential for leptin function and we sought to determine the importance of Jak2 to leptin signaling, at both the molecular and whole-body level. To understand the role of Jak2 phosphorylation in leptin signaling, we used mass spectrometry to identify Jak2 phosphorylation sites and characterize their significance for Jak2 function. We identified numerous phosphorylation sites on Jak2, consistent with an important role for Jak2 phosphorylation during cytokine signaling. Probing the function of these phosphorylation sites in LepRb signaling in cultured cells, we found critical roles for two sites outside of the tyrosine kinase domain: Tyr317 in the FERM domain and Tyr637 in the JH2 domain, exhibited strong regulation of Jak2 activity.;To assess the importance of Jak2 to leptin action in vivo, we replaced the endogenous LepR gene with one that encodes a leptin receptor that binds Jak2 but contains none of LepRb's other functional sites. We found that that leptin-stimulation of Jak2 activity in vivo is sufficient to delay the progression of diabetes compared to mice that have completely non-functional leptin receptor but is not sufficient for other leptin actions. These data suggest at least a minor role for LepRb-associated Jak2 in leptin signaling independent of phosphorylation sites and other motifs on the intracellular tail of LepRb. Overall, our findings underscore the importance of phosphorylation events to Jak2 regulation and demonstrate that Jak2 function alone in vivo, while capable of mediating some leptin functions, is not sufficient to mediate most leptin action.