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Division of Cell and Molecular Biology Department of Biology Boston University Boston, Massachusetts 02215
STAT5b (signal transducer and activator of
transcription 5b) is a key mediator of the effects of plasma GH pulses
on male-specific liver gene expression. STAT5b is activated in liver
cells in vivo by physiological pulses of GH and
then is rapidly deactivated. Investigation of the cellular events
involved in this activation/deactivation cycle using the rat liver cell
line CWSV-1 established that a brief exposure to GH and the associated
activation of JAK2 (Janus kinase 2) tyrosine kinase activity are both
necessary and sufficient to initiate all of the downstream steps
associated with STAT5b activation by tyrosine phosphorylation and the
subsequent deactivation of both JAK2 kinase and STAT5b. JAK2 signaling
to STAT5b at the conclusion of a GH pulse could be sustained by the
protein synthesis inhibitor cycloheximide or by the proteasome
inhibitor MG132, indicating that termination of this JAK2-catalyzed
STAT activation loop requires synthesis of a labile or GH-inducible
protein factor and is facilitated by the proteasome pathway. This
factor may be a phosphotyrosine phosphatase, since the phosphatase
inhibitor pervanadate both sustained GH pulse-induced JAK2 signaling to
STAT5b and blocked the rapid deactivation of phosphorylated STAT5b
(t1/2 = 8.8 ± 0.9 min) seen in its
absence. Finally, the serine kinase inhibitor H7 blocked
down-regulation of JAK2 signaling to STAT5b in a manner that enabled
cells to respond to a subsequent GH pulse without the need for the
3-h interpulse interval normally required for full recovery of GH
pulse responsiveness. Termination of GH pulse-induced STAT5b signaling
is thus a complex process that involves multiple biochemical events.
These are proposed to include the down-regulation of JAK2 signaling to
STAT5b via a cycloheximide- and H7-sensitive step, proteasome-dependent
degradation of a key component or regulatory factor, and
dephosphorylation leading to deactivation of the receptor-kinase
signaling complex and its STAT5b substrate via the action of a
phosphotyrosine phosphatase.
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