title: Rac is a dominant regulator of cadherin-directed actin assembly that is activated by adhesive ligation independently of Tiam1.
abstract: Classic cadherins function as adhesion-activated cell signaling receptors. On adhesive ligation, cadherins induce signaling cascades leading to actin cytoskeletal reorganization that is imperative for cadherin function. In particular, cadherin ligation activates actin assembly by the actin-related protein (Arp)2/3 complex, a process that critically affects the ability of cells to form and extend cadherin-based contacts. However, the signaling pathway(s) that activate Arp2/3 downstream of cadherin adhesion remain poorly understood. In this report we focused on the Rho family GTPases Rac and Cdc42, which can signal to Arp2/3. We found that homophilic engagement of E-cadherin simultaneously activates both Rac1 and Cdc42. However, by comparing the impact of dominant-negative Rac1 and Cdc42 mutants, we show that Rac1 is the dominant regulator of cadherin-directed actin assembly and homophilic contact formation. To pursue upstream elements of the Rac1 signaling pathway, we focused on the potential contribution of Tiam1 to cadherin-activated Rac signaling. We found that Tiam1 or the closely-related Tiam2/STEF1 was recruited to cell-cell contacts in an E-cadherin-dependent fashion. Moreover, a dominant-negative Tiam1 mutant perturbed cell spreading on cadherin-coated substrata. However, disruption of Tiam1 activity with dominant-negative mutants or RNA interference did not affect the ability of E-cadherin ligation to activate Rac1. We conclude that Rac1 critically influences cadherin-directed actin assembly as part of a signaling pathway independent of Tiam1.
authors.affiliation: Division of Molecular Cell Biology, Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Queensland, Australia 4072.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kraemer
authors.forename: Marita
authors.initials: M
authors.lastname: Goodwin
authors.forename: Suzie
authors.initials: S
authors.lastname: Verma
authors.forename: Alpha S
authors.initials: AS
authors.lastname: Yap
authors.forename: Radiya G
authors.initials: RG
authors.lastname: Ali
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins