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.
IQGAPs are an evolutionarily conserved family of proteins that interact with many partners to regulate diverse cellular processes, including cytokinesis , , cell migration , cell proliferation , intracellular signaling , , vesicle trafficking , , and cytoskeletal dynamics , . IQGAP proteins are present in a wide variety of fungi, protist, and animal cells. The majority of vertebrates, including humans, express three related isoforms IQGAP1, IQGAP2, and IQGAP3 (Fig 1). IQGAPs contain several domains that mediate protein–protein interactions (Table 1). While prior reviews have focused on the cellular processes regulated by these interactions , , , , , attention to the roles of IQGAPs at the organism level has been limited. This review summarizes functions of fungal and vertebrate IQGAP proteins in physiology.
IQGAPs scaffold diverse pathways
The multidomain composition of IQGAPs mediates the formation of protein complexes required for cellular processes. For example, interactions of the IQGAP1 calponin homology domain (CHD) with F‐actin and the GAP‐related domain (GRD) with small GTPases regulate the cytoskeleton to promote actin binding or polymerization that regulates cytokinesis , , cell migration , and stability of cell–cell contacts , . IQGAPs also scaffold molecules to form signaling complexes, such as components of the mitogen‐activated protein kinase (MAPK) pathway , . The MAPK signaling cascade is activated in response to stimuli, which leads to sequential phosphorylation from Raf to MAPK‐ERK kinase (MEK) to extracellular signal‐regulated kinase (ERK) . IQGAP1 regulates MAPK signaling by scaffolding several MAPK components, including K‐Ras , B‐Raf , , MEK , and ERK , . These interactions promote ERK activation, which influences myriad cellular processes, ultimately impacting physiology in a variety of tissues. IQGAPs also form complexes with numerous other proteins. These include Ca2+/calmodulin , , , Cdc42 , , , , Rac1 , and actin , , ,  to control the actin cytoskeleton, as well as mTor and Akt kinases , to modulate Akt activation in processes such as cell growth and survival.
Cytokinesis is the culminating event in cell division and is essential for development and tissue maintenance/homeostasis. Defects in cytokinesis can result in aneuploidy, which can lead to developmental defects and has been implicated in cancer . IQGAP proteins have an evolutionarily conserved role in cytokinesis from fungi to mammals. Fungi express a single IQGAP isoform that participates in cytokinesis. A contractile ring, which forms between parent and daughter cells, utilizes myosin motor proteins and the actin cytoskeleton to generate the force necessary to separate cells. Loss‐of‐function studies for several yeast and fungal IQGAPs, including Saccharomyces cerevisiae Iqg1p/Cyk1p , , , Schizosaccharomyces pombe Rng2p , , , and Candida albicans Iqg1p , result in the formation of multinucleated cells, demonstrating a role for IQGAPs in the assembly of the contractile ring and cytokinesis.
Unlike fungi, the amoeba Dictyostelium discoideum has four IQGAP‐like proteins: DGAP1/ddIQGAP1, GAPA/ddIQGAP2, DDB0233055/ddIQGAP3 (Fig 1), and the hypothetical/putative DDB0232202/ddIQGAP4 . Both DGAP1 and GAPA function in cleavage furrow formation in D. discoideum cytokinesis , , . Additionally, GAPA promotes cleavage furrow formation in response to mechanical stress, while DGAP1 inhibits this response . This suggests distinct roles for each protein in response to specific stimuli, that is, DGAP1/biochemical signals and GAPA/mechanosensory inputs.
Less is known about the contribution of IQGAP to cytokinesis in higher eukaryotes. In the nematode Caenorhabditis elegans, RNA interference was employed to identify proteins associated with cleavage furrow formation and cytokinesis. Depletion of the C. elegans IQGAP PES‐7 resulted in the formation of multinucleated germ cells and multinucleated embryos, indicating defects in the completion of meiosis and mitosis . The mid‐body assembles microtubules and other proteins necessary for completion of cell division at the end of cytokinesis. In mammalian cells, IQGAP1 was observed at the mid‐body or contractile ring during cytokinesis in mouse oocytes and embryos , Chinese hamster ovary, as well as human HeLa cells .
Anillin proteins form complexes with actin and other proteins necessary for assembling the actomyosin ring at the cleavage furrow . In S. pombe, Rng2p is recruited to the cleavage site by Mid1p, an anillin‐like protein , . Similarly, in mammalian cells, anillin recruits IQGAP3 to the actomyosin ring . Furthermore, loss‐of‐function studies for IQGAP1 and IQGAP3 demonstrated roles for both proteins in regulating the localization of machinery required for cytokinesis in HeLa cells . In contrast to prior reports, IQGAP1 was not detected at the mid‐body in this study. The reason for the discrepancy is unknown. Nevertheless, depletion of either IQGAP1 or IQGAP3 led to defects in cytokinesis and resulted in the formation of multinucleated cells, with a more pronounced defect upon depletion of both IQGAP1 and IQGAP3, suggesting contributions from both proteins to cytokinesis . Further investigation is required to dissect out the specific roles of IQGAP1 and IQGAP3 in cytokinesis.
Evidence derived from knockout mice and cultured cells has identified roles for IQGAP proteins, particularly IQGAP1, in multiple organs (Table 2). These studies are summarized here.
Podocytes are unique renal epithelial cells that form foot processes which wrap around glomerular capillaries. The processes of neighboring cells are connected by slit diaphragms, specialized intercellular junctions that mediate glomerular filtration  (Fig 2A). Mutations of critical components of slit diaphragms, such as nephrin or podocin, cause the nephrotic syndrome . To further understand slit diaphragm architecture, interactors of the nephrin cytoplasmic domain were examined by mass spectrometry, and IQGAP1 was among the proteins identified . Immunofluorescence micro‐scopy revealed that IQGAP1 co‐distributed with nephrin in the podocyte foot processes. IQGAP1 was also observed in kidney tubules and glomeruli . The participation of IQGAP1 in slit diaphragm function was further suggested by the increased in vitro permeability of a podocyte layer when IQGAP1 is knocked down . These findings and the association of IQGAP1 with several slit diaphragm components (Fig 2A), including nephrin, α‐actinin, αII spectrin, βII spectrin, α‐catenin, and podocin , suggest that IQGAP1 is an integral component of slit diaphragm organization to facilitate filtration.
Although slit diaphragm junctions are different to adherens junctions, they share key adherens junction proteins, including cadherins and catenins . Adherens junctions are formed through cadherin complexes, which are linked intracellularly to the actin cytoskeleton via α‐catenin and β‐catenin . IQGAP1 interacts with several adhesion‐associated proteins, including E‐cadherin (epithelial cadherin) , , N‐cadherin (neuronal cadherin) , VE‐cadherin (vascular endothelial cadherin) , and β‐catenin ,  (Table 1). The interaction of IQGAP1, nephrin, and adherens junction proteins suggests that this multiprotein complex may modulate cadherin‐mediated adhesion and cytoskeletal dynamics in the kidney, consistent with previous reports in cultured epithelial cells .
The peptide hormone angiotensin II, which activates smooth muscle contraction thus contributing to hypertension, can induce podocyte apoptosis . This can cause podocyte injury or depletion, resulting in glomerulosclerosis, a stiffening of the renal glomeruli. Angiotensin II stimulates podocyte apoptosis via MAPK . Interestingly, angiotensin II increases IQGAP1 expression in both rat glomeruli in vivo and cultured podocytes and promotes the interaction of ERK1/2 with IQGAP1 . IQGAP1 knockdown prevents angiotensin II‐induced ERK1/2 activation and apoptosis of podocytes. These findings suggest that IQGAP1 participates in angiotensin II‐mediated apoptosis by modulating MAPK signaling.
IQGAP1 also interacts with phospholipase C epsilon (PLCε1) . Mutations in the PLCE1 gene have been implicated in early‐onset nephrotic syndrome, which leads to end‐stage kidney disease . IQGAP1 co‐immunoprecipitates with PLCε1 from cultured podocytes. However, PLCε1‐null mice do not manifest renal pathology and it is not known whether PLCε1—and its association with IQGAP1—contributes to podocyte function in the development of kidney disease.
The first documentation of IQGAP1 in neuronal cells was published in 2005 . IQGAP1 was observed throughout the cell, along neurites and the developing axon, as well as at the growth cone. Overexpression of IQGAP1 induced neurite outgrowth in NIE‐115 mouse neuroblastoma cells, an effect that was enhanced by phosphorylation of IQGAP1 by protein kinase C ε (PKCε)  (Fig 2Bi). Later work demonstrated that an interaction between IQGAP1 and protein‐tyrosine phosphatase PTPμ is required for neurite outgrowth in E8 chick nasal retinal ganglion cells  (Fig 2Bi). PTPμ is a cell surface receptor that interacts with cadherin/catenin complexes to mediate cell–cell adhesion . PTPμ forms a complex with IQGAP1, N‐cadherin, E‐cadherin, and β‐catenin . Active Cdc42 promotes the association of PTPμ with IQGAP1 and disruption of this interaction with a cell‐permeable peptide inhibitor abrogates PTPμ‐mediated neurite outgrowth. Cdc42 is among the best‐characterized IQGAP1 binding partners (reviewed in , ). IQGAP1 binding stabilizes active Cdc42 to regulate crosslinking of actin filaments, microtubule dynamics, and E‐cadherin‐mediated cell–cell adhesion. The studies described above imply that IQGAP1 facilitates changes in the actin cytoskeleton that are required for neurite outgrowth.
In contrast, decreasing endogenous IQGAP1 with siRNA did not impair nerve growth factor (NGF)‐stimulated neurite outgrowth in PC12 rat pheochromocytoma cells . However, reducing IQGAP3 attenuated neurite outgrowth induced by NGF. PC12 cells do not contain IQGAP2 . Therefore, the effect of knockdown of each IQGAP isoform was examined in hippocampal neurons. Reducing IQGAP2 or IQGAP3, but not IQGAP1, decreased axon elongation . Several factors may account for the different reports of IQGAP1 on neurite outgrowth. These include different cell lines (N1E‐115 versus PC12), different experimental strategies (induction with or without NGF), and different manipulations of IQGAP1 levels (overexpression versus knockdown).
IQGAP1 participates in neuronal proliferation and migration, which allows neurons to properly organize into a functional neural network. In cultured cerebellar neurons, IQGAP1 and lissencephaly 1 (Lis1) co‐localize in axons and growth cones . Lis1 is required for neurogenesis, neuronal survival, and neuronal migration . IQGAP1 co‐immunoprecipitates with Lis1 and knockdown of IQGAP1 impairs neuronal motility . Further, neuronal cells contain a multiprotein complex containing active Cdc42, Lis1, IQGAP1, and CLIP‐170, which appears necessary for optimal motility of neurons (Fig 2Bii). In migrating epithelial cells, IQGAP1 accumulates at the leading edge and associates with CLIP‐170, linking Cdc42 and the cortical actin cytoskeleton to the microtubule network (reviewed in ). In cultured cerebellar neurons, increasing intracellular free Ca2+ concentrations ([Ca2+]i) promoted the interaction of Lis1 with IQGAP1 and active Cdc42, suggesting IQGAP1 is a scaffold through which Lis1 links Ca2+ influx to Cdc42 and the cytoskeleton . These results are consistent with previous studies showing Ca2+/calmodulin binding to IQGAP1 regulates its interactions (reviewed in ).
Adult neurogenesis is the process by which neurons are generated from neural stem cells and progenitor cells. Neural progenitor cells (NPCs) migrate into niches and differentiate into neuronal precursors. Vascular endothelial growth factor (VEGF) stimulates this process . In the absence of IQGAP1, VEGF was unable to stimulate migration of NPCs . Consistent with these results, IQGAP1‐null mice exhibit a delay in NPC differentiation. Cdc42, Rac1, and Lis1 binding to IQGAP1 is enhanced in VEGF‐stimulated NPC migration . This study supports a model in which IQGAP1 acts as an effector of a VEGF‐dependent migratory signal for neural progenitor cells.
IQGAP1 contributes to the regulation of microtubules and the actin cytoskeleton that determines dendritic shape and morphology. Dendritic spines are actin‐rich protrusions from a neuron that are responsible for transmission of signals from presynaptic neurons. The spine head connects to the shaft of the dendrite via a neck. Reduction of IQGAP1 in hippocampal neurons decreases the total number of dendrite tips, without significantly altering total dendrite length . Moreover, in the rat hippocampus, the IQGAP1 CHD promotes spine head formation through interactions with the neural Wiskott–Aldrich syndrome protein (N‐WASP)–actin‐related protein 2/3 (Arp 2/3) complex, while the IQGAP1 GRD is essential for stalk extension  (Fig 2Biii). Disruption of the association between IQGAP1 and N‐cadherin removes IQGAP1 from hippocampal dendritic spines heads . Importantly, IQGAP1−/− mice have decreased spine density and number in brain areas involved in cognition, emotion, and motivation . IQGAP1−/− mice also have long‐term memory deficits, but anxiety and depression‐like behavior are unaffected. Loss of dendritic spines are major contributing factors to psychiatric illness, such as schizophrenia and depression, and neurodegenerative disorders, such as Alzheimer's disease , and it is tempting to speculate that IQGAP1 may participate in the pathophysiology of these conditions.
Repeated seizures in temporal lobe epilepsy induce loss of neurons, especially from the CA1 and CA3 areas of the hippocampus. In a mouse model of epilepsy induced by pyramidal cell degeneration in the CA3 region, IQGAP1 expression was upregulated in CA1 pyramidal neurons . Detailed analysis indicated that IQGAP1 is increased in uncommitted neural stem cells, leading the authors to speculate that IQGAP1 may contribute to the etiology of epileptogenesis. While additional studies are required to validate this hypothesis, the evidence implicating IQGAP1 in neurite outgrowth, spine development, synaptic plasticity, memory formation, and dendrite formation strongly supports a fundamental role for IQGAP1 in brain function.
The cardiovascular system
Excessive pressure on the heart activates intracellular signaling pathways that regulate cardiac morphology. Although IQGAP1‐null mice have normal basal heart function, prolonged pressure overload leads to unfavorable cardiac remodeling with thinning of the ventricular walls, decreased contractility, and increased apoptosis . Cardiac pressure overload activates focal adhesion kinase (FAK), which modulates ERK and Akt signaling that control cardiac remodeling . Deletion of the non‐receptor tyrosine kinase FAK from cardiac myocytes induces left ventricle thinning and blocks ERK activation . Analogous to FAK, IQGAP1 modulates ERK and Akt activation in response to cardiac pressure overload . At the molecular level, long‐term (4‐day) transverse aortic band‐induced chronic pressure overload of wild‐type mouse cardiomyocytes (heart muscle cells) stimulates activation of MEK and ERK, which promote proliferation, and Akt, a kinase that promotes survival . By contrast, MEK, ERK, and Akt activation were abrogated in mice deficient in IQGAP1 . Pressure overload upregulates melusin, a muscle‐specific protein . An IQGAP1–melusin complex mediates ERK activation in response to pressure overload  (Fig 2C). Additionally, IQGAP1 contribution to cardiac function was demonstrated with transgenic mice overexpressing melusin in the heart and double‐transgenic mice that overexpress melusin, but lack IQGAP1. In the absence of IQGAP1, ERK activity was reduced in response to pressure overload and apoptotic death was increased in response to stress, demonstrating a role for IQGAP1 in cardiomyocyte survival . Taken together, these observations implicate IQGAP1 as a signaling platform in cardiac remodeling and morphology.
IQGAP1 influences blood vessel formation. VEGF affects virtually all aspects of blood vessel formation and function. IQGAP1 binds to the VEGF receptor 2 (VEGFR2) and is necessary for VEGF‐stimulated endothelial cell migration and proliferation  (Fig 2Di). These observations imply that IQGAP1 scaffolds VEGFR2 signaling in maintenance and repair of blood vessels. Subsequent studies showed that the IQGAP1/VEGFR2 interaction regulates angiogenesis. For example, IQGAP1 knockdown suppresses VEGF‐stimulated angiogenesis in an in vivo model of chicken chorioallantoic membrane . Additional evidence linking IQGAP1 to angiogenesis is derived from studies in mice. Blood vessel formation in response to injury is impaired in mice lacking IQGAP1 . Further, IQGAP1 expression is increased in angiogenesis following ischemia  and overexpression of IQGAP1 significantly increased angiogenesis in an in vivo mouse tumor model . Finally, IQGAP1‐null mice have reduced recovery of blood flow to the leg after hindlimb ischemia , further demonstrating the contribution of IQGAP1 to angiogenesis.
Vascular endothelial cells form the barrier between blood and tissues, and disruption of the barrier can result in acute systemic inflammatory diseases. Reduction of IQGAP1 disrupts vascular endothelial barrier integrity . Integrins are important mediators of endothelial barrier function. Mice lacking integrin β3 have increased endothelial blood vessel leak in response to VEGF‐stimulation . IQGAP1 binds integrin β3, and IQGAP1‐null mice have reduced localization of integrin αvβ3 to the cell–cell junction and increased lung vascular permeability  (Fig 2Dii). Multiple cytoskeletal signaling proteins, including microtubule plus end binding protein 1 (EB1) and cortactin, control endothelial permeability. A complex comprising IQGAP1, EB1, and cortactin links the actin and microtubule cytoskeletons to strengthen endothelial barrier . Barrier integrity is also affected by shear stress, the mechanical force exerted on endothelial cells by the flow of blood. IQGAP1 is essential for maintaining endothelial cell alignment under shear stress . Adhesion and alignment of endothelial cells exposed to shear stress is impaired by IQGAP1 knockdown, suggesting that IQGAP1 stabilizes adherens junctions under blood flow. By controlling blood vessel formation and barrier integrity, IQGAP1 is a critical integrator of multiple vascular processes.
Asthma is a chronic inflammatory disease that affects ~235 million people and results from airway smooth muscle contraction. Exercise, allergens, microbes, or other stimuli activate the parasympathetic nervous system, leading to release of acetylcholine and histamine, which activate receptors on airway smooth muscle cells to promote contraction  (Fig 2E). These receptors induce Ca2+ release from intracellular stores and RhoA activation, resulting in myosin light chain (MLC) phosphorylation, enhancing the interaction of myosin with actin, thereby promoting airway smooth muscle cell contractility .
IQGAP1 modulates this process  (Fig 2E). IQGAP1 co‐immunoprecipitates with RhoA and p190A‐RhoGAP, a protein that inactivates RhoA, from airway smooth muscle cells. Knockdown of IQGAP1 decreases the RhoA/p190A–RhoGAP co‐localization. Consistent with these results, IQGAP1−/− mice have enhanced airway responsiveness, and increased levels of MLC phosphorylation and active RhoA in the posterior trachea . Moreover, IQGAP1 was significantly lower in airway smooth muscle biopsies from patients with asthma than from healthy controls. Collectively, these data imply that IQGAP1 may contribute to the severity of asthma by controlling airway smooth muscle contractility.
Increased blood glucose concentration induces insulin release from pancreatic β‐cells. Glucose enters the β‐cells where it is metabolized, leading to a rise in [Ca2+]i, which triggers exocytosis of insulin granules . A complex comprising eight subunits, termed the exocyst, tethers insulin‐containing vesicles inducing release of insulin at the plasma membrane. IQGAP1 co‐immunoprecipitates with the exocyst complex . Knockdown of IQGAP1 significantly reduced the ability of glucose to stimulate insulin secretion from β‐cells (Fig 2F). Another mechanism by which IQGAP1 may contribute to insulin secretion is via Rab27a. IQGAP1 forms a complex with Rab27a , a small GTPase that is highly expressed in pancreatic β‐cells and regulates endocytosis of insulin secretory membranes. Reducing expression of endogenous IQGAP1 with siRNA prevented glucose‐induced redistribution of Rab27a from the cytosol to the plasma membrane . Analysis revealed that an association between IQGAP1 and Rab27a is required for endocytosis of secretory membranes. Thus, IQGAP1 participates in both exocytosis and endocytosis of insulin secretory vesicles in response to glucose stimulation (Fig 2F).
Energy homeostasis and insulin secretion are regulated by AMP‐activated protein kinase (AMPK) . IQGAP1 was recently identified as an interactor of AMPK, and the proteins co‐immunoprecipitated from pancreatic β‐cells . Although there is no evidence that this association contributes to β‐cell function, the preponderance of evidence suggests that IQGAP1 participates in insulin secretion.
IQGAP2 is expressed predominantly in the liver, an organ that is central to glucose regulation. Knockout mouse models implicate IQGAP2 in glucose homeostasis. IQGAP2−/− mice had insulin levels similar to those in wild‐type mice, but lower fasting blood glucose levels and enhanced insulin sensitivity during a glucose tolerance test . IQGAP2 deficiency led to loss of facilitated long‐chain fatty acid synthesis and protection from diet‐induced hepatic steatosis. However, conflicting findings were subsequently reported. Another group observed higher blood glucose and insulin levels in IQGAP2‐null mice . The IQGAP2−/− mice exhibited aberrant hepatic regulation of glycogenolysis, gluconeogenesis, and lipid homeostasis, leading the authors to conclude that IQGAP2 deficiency predisposes to non‐alcoholic fatty liver disease. These differences require further investigation. One notable distinction between the studies was the different genetic backgrounds of the mice, SV129J versus C57BL/6J. While the molecular mechanism is unknown, the collective data argue for the involvement of IQGAP2 in glucose homeostasis.
IQGAP1 as a therapeutic target
Despite advances in chemotherapy, treatment often kills healthy cells, producing severe side effects. Approximately 30% of human neoplasms have mutations in Ras and B‐Raf that overactivate ERK , promoting tumor proliferation and migration. Although therapeutics targeting B‐Raf (e.g., sorafenib, vemurafenib, and dabrafenib) have been developed, responses are highly variable and resistance is common . Therefore, additional molecularly targeted cancer therapeutics are required. IQGAP1 is potentially a new target (Table 2). IQGAP1 is overexpressed in human cancer (reviewed in , ). Overexpression of IQGAP1 is associated with enhanced tumor proliferation, invasion, and angiogenesis . By interacting with several MAPK components, IQGAP1 mediates optimal ERK activation , . Initial evidence suggests that targeting the IQGAP1/MAPK pathway associations is feasible. Treatment of mice with cell‐permeable peptides (corresponding to the WW domain of IQGAP1) disrupts IQGAP1–ERK1/2 interactions and inhibits Ras‐driven tumorigenesis . Importantly, the peptides attenuated proliferation of melanoma cells resistant to the B‐Raf inhibitor vemurafenib.
Neoplastic transformation by Ras and other oncoproteins often relies on the Rho GTPases, Cdc42, and Rac1 . Cdc42 and Rac1 are not mutated in cancer, but deregulation of their function leads to carcinogenesis . IQGAP1 inhibits the intrinsic GTPase activity of Cdc42 and Rac1 to stabilize the GTP‐bound, active forms . Overexpression of IQGAP1 increases the pool of active Cdc42 and Rac1, while knockdown of endogenous IQGAP1 significantly decreases the amount of active Cdc42 and Rac1 in mammalian cells , . A dominant‐negative IQGAP1 construct, which decreases the amount of GTP‐bound Cdc42 in cell lysates , reduces neoplastic transformation of malignant MCF‐7 human breast epithelial cells . These results suggest that blocking the formation of IQGAP1–Cdc42 and IQGAP1–Rac1 complexes will decrease the amount of active Cdc42 and Rac1 in carcinoma cells, reducing tumorigenesis.
Small‐molecule inhibitors that disrupt the binding of IQGAP1 to select interactors may be specific chemotherapeutic agents. Targeting a protein–protein interaction (PPI) with a small molecule was thought to be difficult due the large, flat surface areas involved in binding. However, the dynamic PPI interface provides more opportunities for small molecule binding than traditional ‘druggable’ binding pockets . Several small‐molecule PPI inhibitors are at various stages of development, including phase III clinical trials . As IQGAP1 is an oncogene, but is not required for viability , it is an attractive molecule for the development of targeted chemotherapy (Table 2).
Antibiotics are essential for treating bacterial infection. Typically, antibiotics target bacterial enzymes to inhibit processes such as cell‐wall synthesis and protein translation. However, bacteria frequently develop resistance to antibiotics. Novel strategies to combat infection are needed.
Most microbial pathogens usurp signaling pathways of the host cell, particularly cytoskeletal dynamics . Bacterial pathogens manipulate the cytoskeleton to invade the host cell, move within the cell, form vacuoles, and avoid phagocytosis. The role of IQGAP1 in regulation of the cytoskeleton led to investigation of its participation in microbial infection (Table 2). The best‐characterized examples include Escherichia coli, which usurps IQGAP1 to promote formation of actin pedestals ,  and disassembly of adherens junctions , and Salmonella typhimurium, which injects proteins that ‘hijack’ IQGAP1 to modulate the cytoskeleton for invasion into host cells , , . More recently, Chlamydia pneumonia  and Pseudomonas aeruginosa  were observed to regulate IQGAP1 expression to alter cell adhesion and migration. Potentially, inhibition of IQGAP1 interactions with bacterial proteins could control bacterial infection. A benefit of targeting a host protein is the reduced likelihood of mutation, which commonly occurs with antibiotics directed at bacterial proteins. Disrupting a host protein may produce systemic side effects. The benefits of treatment versus off‐target effects are a fundamental question in the therapy of many diseases. Nevertheless, in light of the increasing problem of antibiotic resistance and the lack of new antibiotics coming to market , alternative strategies may yield promising results.
During their life cycle, viruses utilize host‐cell proteins to mediate entry, replication and budding of viral particles to establish and maintain infection . IQGAP1 interacts with several viral proteins, including Ebola virus protein VP40 , classical swine fever virus (CSFV) core protein , and Moloney murine leukemia virus (M‐MuLV) matrix protein  (Table 2). Mutations of these viral proteins that prevent interaction with IQGAP1 or depletion of IQGAP1 from infected cells interfered with viral life cycle. IQGAP1 also forms a complex with host protein TSG101 , which mediates release of the Marburg virus . Depletion of IQGAP1 reduced the release of Marburg virus particles. These findings suggest that IQGAP1 plays a critical role in the life cycle of several viruses and is a potential target for antiviral medication.
Accumulating evidence supports diverse roles for IQGAPs in vertebrates. At the molecular level, IQGAPs scaffold multiprotein complexes that regulate similar processes in different tissues. For example, modulation of cytoskeletal dynamics by the association of IQGAP1 with actin, small GTPases and microtubule binding proteins is critical for controlling tissue integrity and morphology. This role is evident in organizing renal slit diaphragms for glomerular filtration , , controlling neural cell morphology for coordinating neural networks , , , , regulating neural cell migration , , , and maintaining endothelial integrity and stability for barrier functions of blood vessels , , , , . Another conserved role for IQGAPs across tissues is the scaffolding of cell signaling pathways, such as MAPK. IQGAP1 enhances activation of MAPK, but different tissues may have different responses. In the kidney, angiotensin II enhances IQGAP1‐regulated MAPK signaling to contribute to apoptosis , whereas pressure overload of cardiomyocytes promotes IQGAP1‐regulated activation of MAPK that leads to cardiac hypertrophy and survival , . IQGAP1 association with proteins or receptors that have restricted tissue expression may mediate specific cellular responses. For example, the interaction of the muscle‐specific protein melusin with IQGAP1 enhances MAPK signaling in cardiomyocytes in response to pressure overload .
Although the functions of IQGAP1 have been evaluated in several tissues, the unique, redundant, or complementary roles for IQGAP1, IQGAP2, and IQGAP3 require further investigation. Unique functions may be conferred by the distinct tissue expression of IQGAP isoforms. IQGAP1 is ubiquitously expressed, IQGAP2 is predominantly expressed in liver, while IQGAP3 expression is mainly in the brain . Variations in IQGAP isoform sequence may also contribute to specialized IQGAP functions. The amino acid sequences of IQGAP2 and IQGAP3 are 62 and 59%, respectively, identical to IQGAP1. Therefore, it is possible that IQGAPs are differentially regulated through specific post‐translational modifications at residues that are not conserved among all three proteins. For example, quantitative phosphoproteomics studies have identified phosphorylation of IQGAP1 at Ser‐330 , , a residue that is not conserved in IQGAP2 or IQGAP3. Further, while IQGAPs share some binding partners, including calmodulin , , ,  and F‐actin , , , , differences have been reported. Although both IQGAP1 and IQGAP3 associate with ERK proteins, IQGAP3 binds only ERK1 , while IQGAP1 interacts with both ERK1  and ERK2 . Additionally, IQGAP3 co‐immunoprecipitates with anillin, whereas IQGAP1 and IQGAP2 do not . Anillin recruits IQGAP3 for specific roles in cytokinesis, yet IQGAP1 may play a complementary role in this process as loss of either IQGAP1 or IQGAP3 leads to defects in cytokinesis. Isoform‐specific knockout studies, including tissue specific knockouts, are needed to elucidate the biological roles of the three IQGAP proteins.
IQGAP1 is overexpressed in a variety of cancers , . Potentially, inhibitors of IQGAP1 functions could prevent tumor invasion, proliferation, and migration. Preliminary studies targeting IQGAP1 are encouraging , but efficacy in humans and potential side effects need to be established. In the 20 years since their discovery, the identified roles of IQGAP proteins have expanded from cytoskeletal regulators to modulators of diverse functions in several organs. We look forward to future studies that expand upon the distinct roles of IQGAPs in physiology and disease.
Sidebar A: In need of answers
Do IQGAP1, IQGAP2, and IQGAP3 have differential roles in specific tissues? Do the three IQGAPs have unique, redundant, or complementary functions in physiology?
What regulates the interactions of IQGAPs with specific binding partners? Are these complexes tissue specific and/or IQGAP isoform specific? How do IQGAP protein complexes influence cancer, microbial infection, and other diseases?
Conflict of interest
The authors declare that they have no conflict of interest.
We apologize to those authors whose primary work was omitted due to space restrictions. This work was supported by the Intramural Research Program of the National Institutes of Health.
FundingIntramural Research Program of the National Institutes of Health
See the Glossary for abbreviations used in this article.
- AMP‐activated protein kinase
- actin‐related proteins 2/3
- intracellular free calcium concentration
- calponin homology domain
- classical swine fever virus
- microtubule plus end binding protein 1
- extracellular signal‐regulated kinase
- focal adhesion kinase
- GTPase‐activating protein
- guanine nucleotide exchange factor
- GAP‐related domain
- protein sequences containing Iso/Leu and Gln residues
- lissencephaly 1
- Moloney murine leukemia virus
- mitogen‐activated protein kinase
- MAPK/ERK kinase
- myosin light chain
- myosin light chain kinase
- myosin light chain phosphatase
- nerve growth factor
- Neuronal Wiskott–Aldrich syndrome protein
- protein kinase C ε
- phospholipase C ε1
- protein–protein interaction
- protein‐tyrosine phosphatase μ
- RasGAP_C‐terminus domain
- receptor tyrosine kinase
- vascular endothelial growth factor
- vascular endothelial growth factor receptor 2
- tryptophan‐containing protein domain
- Published 2015. This article is a U.S. Government work and is in the public domain in the USA