IQGAP1 regulates cell motility by linking growth factor signaling to actin assembly.
IQGAP1 has been implicated as a regulator of cell motility because its overexpression or underexpression stimulates or inhibits cell migration, respectively, but the underlying mechanisms are not well understood. Here, we present evidence that IQGAP1 stimulates branched actin filament assembly, which provides the force for lamellipodial protrusion, and that this function of IQGAP1 is regulated by binding of type 2 fibroblast growth factor (FGF2) to a cognate receptor, FGFR1. Stimulation of serum-starved MDBK cells with FGF2 promoted IQGAP1-dependent lamellipodial protrusion and cell migration, and intracellular associations of IQGAP1 with FGFR1--and two other factors--the Arp2/3 complex and its activator N-WASP, that coordinately promote nucleation of branched actin filament networks. FGF2 also induced recruitment of IQGAP1, FGFR1, N-WASP and Arp2/3 complex to lamellipodia. N-WASP was also required for FGF2-stimulated migration of MDBK cells. In vitro, IQGAP1 bound directly to the cytoplasmic tail of FGFR1 and to N-WASP, and stimulated branched actin filament nucleation in the presence of N-WASP and the Arp2/3 complex. Based on these observations, we conclude that IQGAP1 links FGF2 signaling to Arp2/3 complex-dependent actin assembly by serving as a binding partner for FGFR1 and as an activator of N-WASP.
Benseñor
Lorena B
LB
Department of Biology, University of Virginia, Charlottesville, VA 22904, USA.
Kan
Ho-Man
HM
Wang
Ningning
N
Wallrabe
Horst
H
Davidson
Lance A
LA
Cai
Ying
Y
Schafer
Dorothy A
DA
Bloom
George S
GS
D051377:Actin-Related Protein 2 / Q000378:metabolism; D051378:Actin-Related Protein 3 / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism / Q000502:physiology*
D051377:Actin-Related Protein 2; D051378:Actin-Related Protein 3; D000199:Actins; C101203:IQ motif containing GTPase activating protein 1; D017468:Receptors, Fibroblast Growth Factor; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020703:ras GTPase-Activating Proteins; D016222:Fibroblast Growth Factor 2