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Mol Cell Biol, July 1998, p. 3718-3726, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Differential Effects of Protein Kinase A on Ras
Effector Pathways
Marsha J.
Miller,1
Lise
Rioux,1
Gregory V.
Prendergast,1
Sarah
Cannon,2
Michael A.
White,3 and
Judy L.
Meinkoth1 *
Department of Medicine and Therapeutics,
University College Dublin, Dublin 7, Ireland2;
Department of Cell Biology and Neuroscience, University of
Texas Southwestern Medical Center, Dallas, Texas
752353; and
Department of Pharmacology,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania 19104-60841
Received 17 December 1997/Returned for modification 1 February
1998/Accepted 26 March 1998
Ras mutants with the ability to interact with different effectors
have played a critical role in the identification of Ras-dependent signaling pathways. We used two mutants, RasS35 and
RasG37, which differ in their ability to bind Raf-1, to
examine Ras-dependent signaling in thyroid epithelial cells. Wistar rat
thyroid cells are dependent upon thyrotropin (TSH) for growth. Although
TSH-stimulated mitogenesis requires Ras, TSH activates protein kinase A
(PKA) and downregulates signaling through Raf and the mitogen-activated protein kinase (MAPK) cascade. Cells expressing RasS35, a
mutant which binds Raf, or RasG37, a mutant which binds
RalGDS, exhibited TSH-independent proliferation. RasS35
stimulated morphological transformation and anchorage-independent growth. RasG37 stimulated proliferation but not
transformation as measured by these indices. TSH exerted markedly
different effects on the Ras mutants and transiently repressed MAPK
phosphorylation in RasS35-expressing cells. In contrast,
TSH stimulated MAPK phosphorylation and growth in cells expressing
RasG37. The Ras mutants, in turn, exerted differential
effects on TSH signaling. RasS35 abolished TSH-stimulated
changes in cell morphology and thyroglobulin expression, while
RasG37 had no effect on these activities. Together, the
data indicate that cross talk between Ras and PKA discriminates between
distinct Ras effector pathways.
*
Corresponding author. Mailing address: Department of
Pharmacology, University of Pennsylvania School of Medicine, 36th St. and Hamilton Walk, Philadelphia, PA 19104-6084. Phone: (215) 898-1909. Fax: (215) 573-2236. E-mail:
meinkoth{at}pharm.med.upenn.edu.
Mol Cell Biol, July 1998, p. 3718-3726, Vol. 18, No. 7
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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