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Interleukin-3-Induced Activation of the JAK/STAT Pathway Is
Prolonged by Proteasome Inhibitors
Bernard A. Callus and
Bernard Mathey-Prevot
From the Department of Pediatric Oncology, Dana-Farber Cancer
Institute, Boston, MA.
One facet of cytokine receptor signaling involves the activation of
signal transducers and activators of transcription (STATs). STATs are
rapidly activated via tyrosine phosphorylation by Janus kinase (JAK)
family members and subsequently inactivated within a short period. We
investigated the effect of proteasome inhibition on interleukin-3
(IL-3) activation of the JAK/STAT pathway following stimulation of
Ba/F3 cells. Treatment of Ba/F3 cells with the proteasome inhibitor,
N-acetyl-L-leucinyl-L-leucinyl-norleucinal (LLnL), led to stable tyrosine phosphorylation of the IL-3 receptor, beta common ( c), and STAT5 following stimulation. The effects of
LLnL were not restricted to the JAK/STAT pathway, as Shc and mitogen-activated protein kinase (MAPK) phosphorylation were also prolonged in LLnL-treated cells. Further investigation showed these
stable phosphorylation events were the result of prolonged activation
of JAK2 and JAK1. These observations were confirmed using pharmacologic
inhibitors. In the presence of LLnL, stable phosphorylation of STAT5
and c was abrogated if the tyrosine kinase inhibitor, staurosporine,
was added. The effect of staurosporine on STAT5 phosphorylation could
be overcome if the phosphatase inhibitor, vanadate, was also added,
suggesting phosphorylated STAT5 could be stabilized by phosphatase, but
not by proteasome inhibition per se. These observations are consistent
with the hypothesis that proteasome-mediated protein degradation can
modulate the activity of the JAK/STAT pathway by regulating the
deactivation of JAK.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3182-3192
© 1998 by The American Society of Hematology.
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