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Molecular and Cellular Biology, November 1998, p. 6245-6252, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Synergistic Regulation of Schwann Cell
Proliferation by Heregulin and Forskolin
Mohammed
Rahmatullah,
Allen
Schroering,
Katrina
Rothblum,
Richard C.
Stahl,
Bobbi
Urban, and
David J.
Carey*
Henry Hood Research Program, Weis Center for
Research, Penn State College of Medicine, Danville, Pennsylvania
17822-2613
Received 6 May 1998/Returned for modification 18 June 1998/Accepted 3 August 1998
A peptide corresponding to the epidermal growth factor homology
domain of
-heregulin stimulated autophosphorylation of the heregulin
receptors erbB2 and erbB3 in Schwann cells and activation of the
mitogen-activated protein (MAP) kinases ERK1 and ERK2. Heregulin-dependent activation of PAK65, a component of the
stress-activated signaling pathway, ribosomal S6 kinase, and a cyclic
AMP (cAMP) response element binding protein (CREB) kinase, identified
as p95RSK2, was also observed. Receptor
phosphorylation and activation of these kinases in response to
heregulin occurred in the absence of forskolin stimulation and were not
augmented in cells treated with forskolin, a direct activator of
adenylyl cyclase. Schwann cell proliferation in response to heregulin
was observed only when the cells were also exposed to an agent that
elevates cAMP levels. In the absence of heregulin, elevation of cAMP
levels failed to stimulate Schwann cell proliferation. Forskolin
significantly enhanced heregulin-stimulated expression of cyclin D and
phosphorylation of the retinoblastoma gene product. In cells treated
with both heregulin and forskolin there was a sustained accumulation of phospho-CREB, which was not observed in cells treated with either agent
alone. Heregulin and forskolin synergistically activated transcription
of a cyclin D promoter construct. These results demonstrate that
heregulin-stimulated activation of MAP kinase is not sufficient to
induce maximal Schwann cell proliferation. Expression of critical cell
cycle regulatory proteins and cell division require activation of both
heregulin and cAMP-dependent processes.
*
Corresponding author. Mailing address: Henry Hood
Research Program, Weis Center for Research, Penn State College of
Medicine, Danville, PA 17822-2613. Phone: (717) 271-6679. Fax: (717)
271-6701. E-mail: djc{at}psghs.edu.
Molecular and Cellular Biology, November 1998, p. 6245-6252, Vol. 18, No. 11
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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