Get to grips: steering local actin dynamics with IQGAPs

Abstract

IQGAPs are actin-binding proteins that scaffold numerous interaction partners, transmitting extracellular signals that influence mitogenic, morphological and migratory cell behaviour. However, the precise mechanisms by which IQGAP proteins influence actin dynamics and actin filament structures have been elusive. Now that IQGAP1 has emerged as a potential key regulator of actin-cytoskeletal dynamics by recruiting both the actin related protein (Arp)2/3 complex and/or formin-dependent actin polymerizing machineries, we propose that IQGAP1 might coordinate the function of mechanistically different actin nucleators for cooperative localized actin filament production in various cellular processes.

Figure 1

Upstream regulators of IQGAP proteins. Various plasma membrane receptors such as G-protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and integrins signal towards IQGAP (green) proteins through direct interaction or the activation of small GTPases and protein kinase C (PKC). IQGAP becomes activated through phosphorylation and conformational changes at its carboxyl terminus. CHD, calponin homology domain; CR3, complement receptor 3; DBR, diaphanous binding region; EGF, epidermal growth factor; FGF, fibroblast growth factor; GRD, Gap related domain; IQGAPs, proteins containing calmodulin-binding IQ motifs and with homology to GTPase activating proteins (GAPs); NGF, nerve growth factor; VEGF, vascular endothelial growth factor; WW, domain with two conserved Trp (W) residues.

Figure 2

Model of IQGAP1-dependent regulation of N-WASp and Arp2/3. N-WASp (dark blue) is shown in its autoinhibited conformation. IQGAP1 (green) and GTP-Cdc42 bind to N-WASp to relieve autoinhibition. The open conformation of N-WASp stimulates the Arp2/3 complex and promotes branched actin filament polymerization. In addition, IQGAP1 might also support the open conformation of N-WASp through stabilization of active Cdc42. Arp2/3, actin related protein 2/3; CHD, calponin homology domain; DBR, diaphanous binding region; EVH1, Ena/VASP-homology 1; GRD, Gap related domain; IQGAPs, proteins containing calmodulin-binding IQ motifs and with homology to GTPase activating proteins (GAPs); N-WASp, neural-Wiskott–Aldrich syndrome protein; VCA, verprolin-connecting-acidic domain; WW, domain with two conserved Trp (W) residues.

Figure 3

Model of IQGAP1-dependent regulation of Diaphanous 1. GTP-bound RhoA relieves autoinhibition of Dia1 (orange) between the diaphanous autoregulatory domain (DAD) and the armadillo repeat region (ARR). RhoA-GTP is rapidly hydrolysed. In the presence of IQGAP1 (green), the ARR of Dia1 binds to the diaphanous binding region (DBR) of IQGAP1 and stabilizes Dia1 in its active conformation. Dimerization of Dia1 and of IQGAP1 is not illustrated. CHD, calponin homology domain; FH2, formin homology 2; Dia1, Diaphanous 1; GBD, GTPase-binding domain; GRD, Gap related domain; IQGAPs, proteins containing calmodulin-binding IQ motifs and with homology to GTPase activating proteins (GAPs); WW, domain with two conserved Trp (W) residues.

Dominique T. Brandt

Robert Grosse