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J. Biol. Chem., Vol. 276, Issue 14, 10839-10846, April 6, 2001
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From the Department of Cell Biology, University Medical Center
Utrecht and Institute of Biomembranes, Heidelberglaan 100, AZU-G02.525, 3584 CX Utrecht, The Netherlands
The growth hormone receptor (GHR)
intracellular domain contains all of the information required for
signal transduction as well as for endocytosis. Previously, we
showed that the proteasome mediates the clathrin-mediated endocytosis
of the GHR. Here, we present evidence that the proteasomal inhibitor
MG132 prolongs the GH-induced activity of both GHR and JAK2, presumably
through stabilization of GHR and JAK2 tyrosine phosphorylation. If
proteasomal inhibitor was combined with ligand in an
endocytosis-deficient GHR mutant, the same phenomenon occurred
indicating that proteasomal action on tyrosine dephosphorylation is
independent of endocytosis. Experiments with a GHR-truncated tail
mutant (GHR-(1-369)) led to a prolonged JAK2 phosphorylation caused by
the loss of a phosphatase-binding site. This raised the question of
what happens to the signal transduction of the GHR after its
internalization. Co-immunoprecipitation of GH·GHR complexes
before and after endocytosis showed that JAK2 as well as other
activated proteins are bound to the GHR not only at the cell surface
but also intracellularly, suggesting that the GHR signal transduction
continues in endosomes. Additionally, these results provide
evidence that GHR is present in endosomes both in its full-length and
truncated form, indicating that the receptor is down-regulated by the proteasome.
The Signal Transduction of the Growth Hormone Receptor Is
Regulated by the Ubiquitin/Proteasome System and Continues After
Endocytosis*
*
This work was supported by Grant NWO-902-68-244 from The
Netherlands Organization for Scientific Research and by European Union
Network Grant ERBFMRXCT96-0026.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 31 30-2506476;
Fax: 31 30-2541797; E-mail: strous@med.uu.nl.
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