Volume 271,
Number 21,
Issue of May 24, 1996 pp. 12669-12673
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Identification of
Tyrosine Residues in the Intracellular Domain of the Growth Hormone
Receptor Required for Transcriptional Signaling and Stat5 Activation
(Received for publication, November 27, 1995; and in revised form, February 13, 1996)
Lone H.
Hansen
,
Xinzhong
Wang
,
John
J.
Kopchick
,
Pierre
Bouchelouche
,
Jens H.
Nielsen
,
Elisabeth D.
Galsgaard
,
Nils
Billestrup
The binding of growth hormone (GH) to its receptor results in
its dimerization followed by activation of Jak2 kinase and tyrosine
phosphorylation of the GH receptor itself, as well as Jak2 and the
transcription factors Stat1, -3, and -5. In order to study the role of
GH receptor tyrosine phosphorylation in intracellular signaling, we
constructed GH receptors in which combinations of tyrosines were
mutated to phenylalanines. We identified three tyrosine residues at
positions 534, 566, and 627 that were required for activation of
GH-stimulated transcription of the serine protease inhibitor (Spi) 2.1
promoter. Any of these three tyrosines is able to independently mediate
GH-induced transcription, indicating redundancy in this part of the GH
receptor. Tyrosine phosphorylation was not required for GH stimulation
of mitogen-activated protein (MAP) kinase activity or for GH-stimulated
Ca
channel activation since these pathways were
normal in cells expressing a GH receptor in which all eight
intracellular tyrosines were mutated to phenylalanines. Activation of
Stat5 by GH was, however, abolished in cells expressing the GH receptor
lacking intracellular tyrosines. This study demonstrates that specific
tyrosines in the GH receptor are required for transcriptional signaling
possibly by their role in the activation of transcription factor Stat5.
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