Rac Downregulates Rho Activity
Open Access
- 29 November 1999
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 147 (5), 1009-1022
- https://doi.org/10.1083/jcb.147.5.1009
Abstract
Using biochemical assays to determine the activation state of Rho-like GTPases, we show that the guanine nucleotide exchange factor Tiam1 functions as a specific activator of Rac but not Cdc42 or Rho in NIH3T3 fibroblasts. Activation of Rac by Tiam1 induces an epithelial-like morphology with functional cadherin-based adhesions and inhibits migration of fibroblasts. This epithelial phenotype is characterized by Rac-mediated effects on Rho activity. Transient PDGF-induced as well as sustained Rac activation by Tiam1 or V12Rac downregulate Rho activity. We found that Cdc42 also downregulates Rho activity. Neither V14Rho or N19Rho affects Rac activity, suggesting unidirectional signaling from Rac towards Rho. Downregulation of Rho activity occurs independently of Rac- induced cytoskeletal changes and cell spreading. Moreover, Rac effector mutants that are defective in mediating cytoskeleton changes or Jun kinase activation both downregulate Rho activity, suggesting that neither of these Rac signaling pathways are involved in the regulation of Rho. Restoration of Rho activity in Tiam1-expressing cells by expression of V14Rho results in reversion of the epithelioid phenotype towards a migratory, fibroblastoid morphology. We conclude that Rac signaling is able to antagonize Rho activity directly at the GTPase level, and that the reciprocal balance between Rac and Rho activity determines cellular morphology and migratory behavior in NIH3T3 fibroblasts.Keywords
This publication has 53 references indexed in Scilit:
- Identification of the stef Gene That Encodes a Novel Guanine Nucleotide Exchange Factor Specific for Rac1Published by Elsevier BV ,1999
- Activation of β1 Integrin Signaling Stimulates Tyrosine Phosphorylation of p190 and Membrane-protrusive Activities at InvadopodiaPublished by Elsevier BV ,1998
- Inhibition of Invasion of Epithelial Cells by Tiam1-Rac SignalingScience, 1997
- Human p21-activated kinase (Pak1) regulates actin organization in mammalian cellsCurrent Biology, 1997
- RAC Regulation of Actin Polymerization and Proliferation by a Pathway Distinct from Jun KinaseScience, 1996
- The Novel Catenin p120casBinds Classical Cadherins and Induces an Unusual Morphological Phenotype in NIH3T3 FibroblastsExperimental Cell Research, 1996
- Rhotekin, a New Putative Target for Rho Bearing Homology to a Serine/Threonine Kinase, PKN, and Rhophilin in the Rho-binding DomainPublished by Elsevier BV ,1996
- Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodiaCell, 1995
- The small GTP-binding protein rac regulates growth factor-induced membrane rufflingCell, 1992
- The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factorsCell, 1992