[Role of the multifunctional Trio protein in the control of the Rac1 and RhoA gtpase signaling pathways].
The small GTPases Cdc42, Rac and RhoA have important regulatory roles in mediating cytoskeletal rearrangements, MAP kinase cascades and induction of G1 cell cycle progression. The activity of the GTPases is regulated by guanine nucleotide exchange factors (GEFs) which accelerate their GDP/GTP exchange rate, and thereby activate them. All the GEFs for the Rho-GTPases family share two conserved domains: the DH domain (for Dbl-homology domain) responsible for the enzymatic activity, and the PH domain, probably responsible for the proper localization of the molecule. Trio is a multifunctional protein that is comprised of two functional Rho-GEFs domains and a serine/threonine kinase domain. We have shown in vitro and in vivo that the first GEF domain (GEFD1) activates Rac1, while the second GEF domain (GEFD2) acts on RhoA. Moreover, the co-expression of both domains induces simultaneously the activation of both GTPases. To our knowledge, this is the first example of a member of the Rho-GEF family, that contains two functional exchange factor domains, with restricted and different specificity. We are currently investigating how these GEF domains are activated, by addressing the role of the PH domains in GTPases activation by Trio. We have shown that: 1) the PH1 of Trio is necessary for Rac activation by the GEFD1; 2) the PH1 of Trio targets the molecule to the cytoskeleton; 3) the GEFD1 domain of Trio binds, in a two-hybrid screen, the actin binding protein filamin. These data suggest that the PH1 targets Trio to the cytoskeleton close to Rac and its effectors, probably via interaction with the actin-binding protein filamin, consistent with a role of Trio in actin cytoskeleton remodeling.
CRBM-CNRS, 1919, Montpellier, France.
J M
JM
Bellanger
O
O
Zugasti
J B
JB
Lazaro
S
S
Diriong
N
N
Lamb
C
C
Sardet
A
A
Debant
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D003599:Cytoskeleton / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D010750:Phosphoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
D020662:Guanine Nucleotide Exchange Factors; D010750:Phosphoproteins; D011994:Recombinant Proteins; C490975:Trio protein, mouse; D017346:Protein Serine-Threonine Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
Rôle de la protéine multifonctionnelle Trio dans le contrôle des voies de signalisation des GTPases Rac1 et RhoA.