Desensitization of the PDGFbeta receptor by modulation of the cytoskeleton: the role of p21(Ras) and Rho family GTPases.
Ligand-induced PDGF-type beta receptor (PDGFbeta-R) autophosphorylation is profoundly suppressed in cells transformed by activated p21(Ras). We report here that the integrity of the actin cytoskeleton is a critical regulator of PDGFbeta-R function in the presence of p21(Ras). Morphological reversion of Balb cells expressing a constitutively activated p21(Ras), with re-formation of actin stress fibers and cytoskeletal architecture, rendering them phenotypically similar to untransformed fibroblasts, allowed recovery of ligand-dependent PDGFbeta-R autophosphorylation. Conversely, disruption of the actin cytoskeleton in Balb/c-3T3 cells obliterated the normal ligand-induced phosphorylation of the PDGFbeta-R. The Rho family GTPases Rac and Rho are activated by p21(Ras) and are critical mediators of cell motility and morphology via their influence on the actin cytoskeleton. Transient expression of wild-type or constitutively active mutant forms of RhoA suppressed ligand-dependent PDGFbeta-R autophosphorylation and downstream signal transduction. These studies demonstrate the necessary role of Rho in the inhibition of PDGFbeta-R autophosphorylation in cells containing activated p21(Ras) and also demonstrate the importance of cell context and the integrity of the actin cytoskeleton in the regulation of PDGFbeta-R ligand-induced autophosphorylation.
Stice
Ligaya L
LL
Cancer Research Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Forman
Lora W
LW
Hahn
Chang S
CS
Faller
Douglas V
DV
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D014638:Vanadates / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000502:physiology*
D000199:Actins; D004791:Enzyme Inhibitors; D008024:Ligands; D014638:Vanadates; D020797:Receptor, Platelet-Derived Growth Factor beta; D016283:Proto-Oncogene Proteins p21(ras); D020741:rho GTP-Binding Proteins