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Department of Physiology (T.-W.L.G., J.L., G.S.C., X.W., C.C.-S., J.S.) and Program in Cellular and Molecular Biology (D.J.M., C.L.H., C.C.-S., J.S.), University of Michigan Medical School, Ann Arbor, Michigan 48109-0622; and Hagedorn Research Laboratory (N.B.), Gentofte, Denmark
Address all correspondence and requests for reprints to: Jessica Schwartz, Ph.D., Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622. E-mail: jeschwar{at}umich.edu
To identify mechanisms by which GH receptors (GHR) mediate downstream
events representative of growth and metabolic responses to GH,
stimulation by GH of c-fos and egr-1
expression and glucose transport activity were examined in Chinese
hamster ovary (CHO) cells expressing mutated GHR. In CHO cells
expressing wild-type GHR (GHR1–638), GH stimulated the
expression of c-fos and egr-1, and
stimulated 2-deoxyglucose uptake, responses also mediated by endogenous
GHR in 3T3-F442A cells. Deletion of the proline-rich box 1 of GHR
(GHR
P) abrogated all of these responses to GH,
indicating that box 1, a site of association of GHR with the tyrosine
kinase JAK2, is crucial for these GH-stimulated responses. As the
C-terminal half of the cytoplasmic domain of GHR is required for
GH-stimulated calcium flux and for stimulation of
spi-2.1 transcription, GHR lacking this sequence
(GHR1–454) were examined. Not only did
GHR1–454 mediate stimulation of c-fos and
egr-1 expression and 2-deoxyglucose uptake, but they
also mediated GH-stimulated transcriptional activation via Elk-1, a
transcription factor associated with the c-fos Serum
Response Element. Thus, the C-terminal half of the cytoplasmic domain
of GHR is not required for GH-stimulated c-fos
transcription, suggesting that increased calcium is not required for
GH-stimulated c-fos expression. In CHO cells lacking all
but five N-terminal residues of the cytoplasmic domain
(GHR1–294), GH did not induce c-fos or
egr-1 expression or stimulate 2-deoxyglucose uptake.
Further, in 3T3-F442A fibroblasts with endogenous GHR, GH-stimulated
c-fos expression and 2-deoxyglucose uptake were reduced
by the tyrosine kinase inhibitors herbimycin A, staurosporine, and P11.
Herbimycin A and staurosporine inhibit JAK2 and tyrosyl phosphorylation
of all proteins stimulated by GH, whereas P11 inhibits the GH-dependent
tyrosyl phosphorylation of only some proteins, including extracellular
signal regulated kinases ERK1 and -2, but not JAK2. Taken together,
these results implicate association of GHR with JAK2 and GH-stimulated
tyrosyl phosphorylation of an additional cellular protein in
GH-stimulated glucose transport and c-fos and
egr-1 expression. These studies also indicate that, in
contrast to spi-2.1, the N-terminal half of the
cytoplasmic domain of GHR is sufficient to mediate stimulation of
c-fos and egr-1 expression and Elk-1
activation, supporting multiple mechanisms for GH signaling to the
nucleus.
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