Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes.
The challenge of 3T3-F442A fibroblasts with growth hormone led to both a decrease in the mobility on SDS/PAGE and activation of the PDE4A cyclic AMP-specific phosphodiesterase isoform PDE4A5. Activation was mediated by a JAK-2-dependent pathway coupled to the activation of phosphatidylinositol 3-kinase and p70S6 kinase. Activation was not dependent on the ability of growth hormone to stimulate ERK2 or protein kinase C or any effect on transcription. Blockade of activation of murine PDE4A5 ablated the ability of growth hormone to decrease intracellular cAMP levels. Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes. It is suggested that activation of PDE4A5 by growth hormone serves as a brake on the differentiation processes.
MacKenzie
S J
SJ
Division of Biochemistry, Davidson and Wolfson Buildings, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
Yarwood
S J
SJ
Peden
A H
AH
Bolger
G B
GB
Vernon
R G
RG
Houslay
M D
MD
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D013006:Growth Hormone / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C095813:Pde4a protein, mouse