IQGAP1 stimulates actin assembly through the N-WASP-Arp2/3 pathway.
IQGAP1 is a conserved modular protein overexpressed in cancer and involved in organizing actin and microtubules in motile processes such as adhesion, migration, and cytokinesis. A variety of proteins have been shown to interact with IQGAP1, including the small G proteins Rac1 and Cdc42, actin, calmodulin, beta-catenin, the microtubule plus end-binding proteins CLIP170 (cytoplasmic linker protein) and adenomatous polyposis coli. However, the molecular mechanism by which IQGAP1 controls actin dynamics in cell motility is not understood. Quantitative co-localization analysis and down-regulation of IQGAP1 revealed that IQGAP1 controls the co-localization of N-WASP with the Arp2/3 complex in lamellipodia. Co-immunoprecipitation supports an in vivo link between IQGAP1 and N-WASP. Pull-down experiments and kinetic assays of branched actin polymerization with N-WASP and Arp2/3 complex demonstrated that the C-terminal half of IQGAP1 activates N-WASP by interacting with its BR-CRIB domain in a Cdc42-like manner, whereas the N-terminal half of IQGAP1 antagonizes this activation by association with a C-terminal region of IQGAP1. We propose that signal-induced relief of the autoinhibited fold of IQGAP1 allows activation of N-WASP to stimulate Arp2/3-dependent actin assembly.
Le Clainche
Christophe
C
Dynamics of Cytoskeleton and Motility Group, CNRS, Gif-sur-Yvette, France.
Schlaepfer
Dominik
D
Ferrari
Aldo
A
Klingauf
Mirko
M
Grohmanova
Katarina
K
Veligodskiy
Alexey
A
Didry
Dominique
D
Le
Diep
D
Egile
Coumaran
C
Carlier
Marie-France
MF
Kroschewski
Ruth
R
D051377:Actin-Related Protein 2 / Q000737:chemistry*; D051378:Actin-Related Protein 3 / Q000737:chemistry*; D000199:Actins / Q000737:chemistry*; D000818:Animals; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D008869:Microtubule-Associated Proteins / Q000737:chemistry; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000737:chemistry; D011485:Protein Binding; D011489:Protein Denaturation; D017434:Protein Structure, Tertiary; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000737:chemistry*; D020703:ras GTPase-Activating Proteins / Q000737:chemistry*
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020703:ras GTPase-Activating Proteins; C076744:cytoplasmic linker protein 170