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Article

Phosphorylation of Jak2 on Ser523 InhibitsJak2-Dependent Leptin ReceptorSignaling

, , , , , , & show all
Pages 4063-4073 | Received 17 Aug 2005, Accepted 08 Mar 2006, Published online: 27 Mar 2023
 

Abstract

The leptin receptor, LRb, and other cytokine receptors are devoid of intrinsic enzymatic activity and rely upon the activity of constitutively associated Jak family tyrosine kinases to mediate intracellular signaling. In order to clarify mechanisms by which Jak2, the cognate LRb-associated Jak kinase, is regulated and mediates downstream signaling, we employed tandem mass spectroscopic analysis to identify phosphorylation sites on Jak2. We identified Ser523 as the first-described site of Jak2 serine phosphorylation and demonstrated that this site is phosphorylated on Jak2 from intact cells and mouse spleen. Ser523 was highly phosphorylated in HEK293 cells independently of LRb-Jak2 activation, suggesting a potential role for the phosphorylation of Ser523 in the regulation of LRb by other pathways. Indeed, mutation of Ser523 sensitized and prolonged signaling by Jak2 following activation by the intracellular domain of LRb. The effect of Ser523 on Jak2 function was independent of Tyr570-mediated inhibition. Thus, the phosphorylation of Jak2 on Ser523 inhibits Jak2 activity and represents a novel mechanism for the regulation of Jak2-dependent cytokine signaling.

View correction statement:
Phosphorylation of Jak2 on Ser523 Inhibits Jak2-Dependent Leptin Receptor Signaling

Supplemental material for this article may be found at http://mcb.asm.org/.

This work was supported by NIH DK56731 and grants from the American Diabetes Association (to M.G.M.), the Cellular and Molecular Biology Core of the Michigan Diabetes Research and Training Center (P60 DK20572), and Joslin's Diabetes and Endocrinology Research Center DK36836 (Proteomics Core laboratory).

We are grateful to Diane Fingar for a critical reading of the manuscript. Thanks go to the laboratory of Christin Carter-Su for sharing their preparation ofα Jak2(PS523).

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