Transforming growth factor-beta-induced mobilization of actin cytoskeleton required signaling by small GTPases Cdc42 and RhoA
2002 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, no 3, 902-914 p.Article in journal (Refereed) Published
Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation in many cell types. The Smad signaling pathway constitutes a main signal transduction route downstream of TGF-beta receptors. We studied TGF-beta-induced rearrangements of the actin filament system and found that TGF-beta 1 treatment of PC-3U human prostate carcinoma cells resulted in a rapid formation of lamellipodia. Interestingly, this response was shown to be independent of the Smad signaling pathway; instead, it required the activity of the Rho GTPases Cdc42 and RhoA, because ectopic expression of dominant negative mutant Cdc42 and RhoA abrogated the response. Long-term stimulation with TGF-beta 1 resulted in an assembly of stress fibers; this response required both signaling via Cdc42 and RhoA, and Smad proteins. A known downstream effector of Cdc42 is p38(MAPK); treatment of the cells with the p38(MAPK) inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), as well as ectopic expression of a kinase-inactive p38(MAPK), abrogated the TGF-beta-induced actin reorganization. Moreover, treatment of cells with the inhibitors of the RhoA target-protein Rho-associated coiled-coil kinase (+)-R-trans-4-(aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide (Y-27632) and 1-5(-isoquinolinesulfonyl)homopiperazine (HA-1077), as well as ectopic expression of kinase-inactive Rho coiled-coil kinase-1, abrogated the TGF-beta 1-induced formation of stress fibers. Collectively, these data indicate that TGF-beta-induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways.
Place, publisher, year, edition, pages
The American Society for Cell Biology , 2002. Vol. 13, no 3, 902-914 p.
Actins/*metabolism, Amides/pharmacology, Animals, Cell Surface Extensions/metabolism, Cytoskeleton/drug effects/*metabolism, DNA-Binding Proteins/genetics/metabolism, Enzyme Inhibitors/pharmacology, Humans, Imidazoles/pharmacology, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinases/antagonists & inhibitors/genetics/metabolism, Protein-Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism, Pyridines/pharmacology, Rats, Recombinant Fusion Proteins/metabolism, Signal Transduction/*physiology, Smad4 Protein, Stress Fibers/metabolism, Trans-Activators/genetics/metabolism, Transforming Growth Factor beta/*metabolism, Tumor Cells; Cultured, cdc42 GTP-Binding Protein/*metabolism, p38 Mitogen-Activated Protein Kinases, rac1 GTP-Binding Protein/metabolism, rhoA GTP-Binding Protein/*metabolism
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-90259DOI: 10.1091/mbc.01–08–0398PubMedID: 11907271OAI: oai:DiVA.org:uu-90259DiVA: diva2:162555