Affiliation:
1. Departments
of Internal Medicine and Molecular and Integrative Physiology,
University of Michigan Medical School, Ann Arbor, Michigan
48109
2. Research Division,
Joslin Diabetes Center, Boston, Massachusetts
02215
Abstract
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 Ser
523
as the first-described site of Jak2 serine phosphorylation and
demonstrated that this site is phosphorylated on Jak2 from intact cells
and mouse spleen. Ser
523
was highly phosphorylated in HEK293
cells independently of LRb-Jak2 activation, suggesting a potential role
for the phosphorylation of Ser
523
in the regulation of LRb
by other pathways. Indeed, mutation of Ser
523
sensitized and
prolonged signaling by Jak2 following activation by the intracellular
domain of LRb. The effect of Ser
523
on Jak2 function was
independent of Tyr
570
-mediated inhibition. Thus, the
phosphorylation of Jak2 on Ser
523
inhibits Jak2 activity and
represents a novel mechanism for the regulation of Jak2-dependent
cytokine
signaling.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
50 articles.
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