Transforming Growth Factor-β–induced Mobilization of Actin Cytoskeleton Requires Signaling by Small GTPases Cdc42 and RhoA

Author:

Edlund Sofia1,Landström Maréne1,Heldin Carl-Henrik1,Aspenström Pontus1

Affiliation:

1. Ludwig Institute for Cancer Research, Biomedical Center, S-751 24 Uppsala, Sweden

Abstract

Transforming growth factor-β (TGF-β) 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-β receptors. We studied TGF-β–induced rearrangements of the actin filament system and found that TGF-β1 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-β1 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 p38MAPK; treatment of the cells with the p38MAPKinhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(pyridyl)1H-imidazole (SB203580), as well as ectopic expression of a kinase-inactive p38MAPK, abrogated the TGF-β–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-β1–induced formation of stress fibers. Collectively, these data indicate that TGF-β–induced membrane ruffles occur via Rho GTPase-dependent pathways, whereas long-term effects require cooperation between Smad and Rho GTPase signaling pathways.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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