Phosphorylation of Jak2 on Ser(523) inhibits Jak2-dependent leptin receptor signaling.
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.
Ishida-Takahashi
Ryoko
R
Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
Rosario
Felicia
F
Gong
Yusong
Y
Kopp
Keely
K
Stancheva
Zlatina
Z
Chen
Xiaohong
X
Feener
Edward P
EP
Myers
Martin G
MG
D000818:Animals; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D053614:Janus Kinase 2; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction; D013379:Substrate Specificity
C515448:LEPR protein, human; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D010768:Phosphoserine; D018698:Glutamic Acid; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2