TY - JOUR
T1 - Differential effects of protein kinase A on Ras effector pathways
AU - Miller, Marsha J.
AU - Rioux, Lise
AU - Prendergast, Gregory V.
AU - Cannon, Sarah
AU - White, Michael A.
AU - Meinkoth, Judy L.
PY - 1998/7
Y1 - 1998/7
N2 - 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, Ras(S35) and Ras(G37), which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells. Wistar rat thyroid cells 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 Ras(S35), a mutant which binds Raf, or Ras(G37), a mutant which binds RalGDS, exhibited TSH-independent proliferation. Ras(S35) stimulated morphological transformation and anchorage-independent growth. Ras(G37) stimulated proliferation but not transformation as measured by these indices. TSH exerted markedly different effects on the Ras mutants and transiently repressed MAKP phosphorylation in Ras(S35) expressing cells. In contrast, TSH stimulated, MAPK phosphorylation and growth in cells expressing Ras(G37). The Ras mutants, in turn, exerted differential effects on TSH signalling. Ras(S35) abolished TSH-stimulated changes in cell morphology and thyroglobulin expression while Ras(G37) had no effect on these activities. Together, the data indicate that cross talk between Pros and PICA discriminates between distinct Ras effector pathways.
AB - 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, Ras(S35) and Ras(G37), which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells. Wistar rat thyroid cells 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 Ras(S35), a mutant which binds Raf, or Ras(G37), a mutant which binds RalGDS, exhibited TSH-independent proliferation. Ras(S35) stimulated morphological transformation and anchorage-independent growth. Ras(G37) stimulated proliferation but not transformation as measured by these indices. TSH exerted markedly different effects on the Ras mutants and transiently repressed MAKP phosphorylation in Ras(S35) expressing cells. In contrast, TSH stimulated, MAPK phosphorylation and growth in cells expressing Ras(G37). The Ras mutants, in turn, exerted differential effects on TSH signalling. Ras(S35) abolished TSH-stimulated changes in cell morphology and thyroglobulin expression while Ras(G37) had no effect on these activities. Together, the data indicate that cross talk between Pros and PICA discriminates between distinct Ras effector pathways.
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U2 - 10.1128/MCB.18.7.3718
DO - 10.1128/MCB.18.7.3718
M3 - Article
C2 - 9632754
AN - SCOPUS:0031835656
SN - 0270-7306
VL - 18
SP - 3718
EP - 3726
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 7
ER -