Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2.
Transforming growth factor-beta (TGF-beta) stimulates cellular proliferation and transformation to a myofibroblast phenotype in vivo and in a subset of fibroblast cell lines. As the Smad pathway is activated by TGF-beta in essentially all cell types, it is unlikely to be the sole mediator of cell type-specific outcomes to TGF-beta stimulation. In the current study, we determined that TGF-beta receptor signaling activates phosphatidylinositol 3-kinase (PI3K) in several fibroblast but not epithelial cultures independently of Smad2 and Smad3. PI3K activation occurs in the presence of dominant-negative dynamin and is required for p21-activated kinase-2 kinase activity and the increased proliferation and morphologic change induced by TGF-beta in vitro.
Wilkes
Mark C
MC
Department of Biochemistry and Molecular Biology, Thoracic Diseases Research Unit, and Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Mitchell
Hugh
H
Penheiter
Sumedha Gulati
SG
Doré
Jules J
JJ
Suzuki
Kaori
K
Edens
Maryanne
M
Sharma
Deepak K
DK
Pagano
Richard E
RE
Leof
Edward B
EB
D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D054462:p21-Activated Kinases
D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D054462:p21-Activated Kinases; C497783:Smad2 protein, mouse; C497791:Smad3 protein, mouse; C515909:Pak2 protein, mouse