The biology of IQGAP proteins: beyond the cytoskeleton

Abstract

IQGAP scaffold proteins are evolutionarily conserved in eukaryotes and facilitate the formation of complexes that regulate cytoskeletal dynamics, intracellular signaling, and intercellular interactions. Fungal and mammalian IQGAPs are implicated in cytokinesis. IQGAP1, IQGAP2, and IQGAP3 have diverse roles in vertebrate physiology, operating in the kidney, nervous system, cardio-vascular system, pancreas, and lung. The functions of IQGAPs can be corrupted during oncogenesis and are usurped by microbial pathogens. Therefore, IQGAPs represent intriguing candidates for novel therapeutic agents. While modulation of the cytoskeletal architecture was initially thought to be the primary function of IQGAPs, it is now clear that they have roles beyond the cytoskeleton. This review describes contributions of IQGAPs to physiology at the organism level.

Keywords: IQGAP1; IQGAP2; IQGAP3; biology; therapeutics.

Figure 1

Tree of IQGAP proteins IQGAP proteins are present in eukaryotes . All contain a GRD. All mammals have five domains: CHD, WW domain, IQ domain, GRD, and RasGAP_C-terminus (RGCT). Domains adapted from the SMART and Pfam databases, tree made as in .

Figure 2

Models for IQGAP1 physiological functions (A) Kidney function. IQGAP1 is involved in podocyte permeability and migration . IQGAP1 forms a complex with nephrin and several adherens junction proteins, including α-actinin, αII spectrin, βII spectrin, α-catenin, and podocin . This complex may influence podocyte spacing and stability through cytoskeletal remodeling. IQGAP1 contributes to renal apoptosis by facilitating angiotensin II-induced Erk activation . (B) Neuronal function. (i) PTPμ, IQGAP1, N-cadherin, E-cadherin, and β-catenin form a complex in ganglion cells . Cdc42 promotes the interaction of IQGAP1 with PTPμ to stimulate actin remodeling and, ultimately, neurite outgrowth. IQGAP1 phosphorylation by PKCε also stimulates neurite outgrowth in neuroblastoma cells . (ii) IQGAP1 forms a complex with active Cdc42, Lis1, and CLIP-170 that appears necessary for cerebellar neuronal motility . (iii) In hippocampal neurons, the IQGAP1/N-WASP/Arp2/3 complex promotes dendritic spine head formation . (C) Cardiac function. Pressure overload on the heart activates focal adhesion kinase (FAK), which signals through MAPK and Akt to regulate cardiomyocyte hypertrophy and survival. MAPK and Akt signaling in this process is regulated by IQGAP1 , . IQGAP1 forms a complex with melusin that mediates MAPK signaling downstream of FAK. The dashed lines depict intermediate signaling events that control Akt and Raf activation from FAK. (D) Vascular endothelial barrier function. (i) IQGAP1 binds to VEGFR2 and regulates endothelial cell migration, proliferation, and angiogenesis , . (ii) Both the IQGAP1/EB1/cortactin complex and the IQGAP1/integrin α_vβ₃ interaction strengthen the endothelial barrier, reducing permeability. (E) Lung function. Stimulation of airway smooth muscle cells induces contraction. Acetylcholine and histamine both activate RhoA and release Ca²⁺ from intracellular stores, which regulate phosphorylation of the regulatory myosin light chain (MLC). Ca²⁺ binds to calmodulin (CaM), which activates MLC kinase (MLCK), catalyzing MLC phosphorylation. Phosphorylated MLC facilitates the interaction of myosin with F-actin, thereby inducing smooth muscle contraction. RhoA stimulates Rho-associated protein kinase (ROCK), which phosphorylates and inhibits MLC phosphatase (MLCP). Together, Ca²⁺ and RhoA favor the phosphorylation of MLC and muscle contraction. IQGAP1 modulates contractility by forming a complex with p190A-RhoGAP and RhoA to inactivate RhoA . Loss of IQGAP1 promotes MLC phosphorylation and enhances airway smooth muscle cell contractility. The dashed lines depict intermediate signaling events that control Ca²⁺ release and RhoA activation downstream of receptors. (F) Insulin secretion. Glucose stimulation of pancreatic β-cells induces release of insulin from secretory vesicles. IQGAP1 interacts with exocyst components to facilitate insulin exocytosis . An IQGAP1–Rab27a complex participates in endocytosis of insulin secretory membranes .