ABSTRACT
The
tyrosine kinase JAK2 is a key signaling protein for at least 20
receptors in the cytokine/hematopoietin receptor superfamily and is a
component of signaling for multiple receptor tyrosine kinases and
several G-protein-coupled receptors. In this study, phosphopeptide
affinity enrichment and mass spectrometry identified serine 523
(Ser523) in JAK2 as a site of phosphorylation. A phosphoserine 523
antibody revealed that Ser523 is rapidly but transiently phosphorylated
in response to growth hormone (GH). MEK1 inhibitor UO126 suppresses
GH-dependent phosphorylation of Ser523, suggesting that extracellular
signal-regulated kinases (ERKs) 1 and/or 2 or another kinase downstream
of MEK1 phosphorylate Ser523 in response to GH. Other ERK activators,
phorbol 12-myristate 13-acetate and epidermal growth factor, also
stimulate phosphorylation of Ser523. When Ser523 in JAK2 was mutated,
JAK2 kinase activity as well as GH-dependent tyrosyl phosphorylation of
JAK2 and Stat5 was enhanced, suggesting that phosphorylation of Ser523
inhibits JAK2 kinase activity. We hypothesize that phosphorylation of
Ser523 in JAK2 by ERKs 1 and/or 2 or other as-yet-unidentified kinases
acts in a negative feedback manner to dampen activation of JAK2 in
response to GH and provides a mechanism by which prior exposure to
environmental factors that regulate Ser523 phosphorylation might
modulate the cell's response to
GH.
E-Cadherin, as a Negative Regulator of Invasive Behavior of Human Trophoblast Cells, Is Down-Regulated by Cyclosporin A Via Epidermal Growth Factor/Extracellular Signal-Regulated Protein Kinase Signaling Pathway1