The IQGAP scaffolds: Critical nodes bridging receptor activation to cellular signaling

Abstract

The scaffold protein IQGAP1 assembles multiprotein signaling complexes to influence biological functions. Cell surface receptors, particularly receptor tyrosine kinases and G-protein coupled receptors, are common IQGAP1 binding partners. Interactions with IQGAP1 modulate receptor expression, activation, and/or trafficking. Moreover, IQGAP1 couples extracellular stimuli to intracellular outcomes via scaffolding of signaling proteins downstream of activated receptors, including mitogen-activated protein kinases, constituents of the phosphatidylinositol 3-kinase pathway, small GTPases, and β-arrestins. Reciprocally, some receptors influence IQGAP1 expression, subcellular localization, binding properties, and post-translational modifications. Importantly, the receptor:IQGAP1 crosstalk has pathological implications ranging from diabetes and macular degeneration to carcinogenesis. Here, we describe the interactions of IQGAP1 with receptors, summarize how they modulate signaling, and discuss their contribution to pathology. We also address the emerging functions in receptor signaling of IQGAP2 and IQGAP3, the other human IQGAP proteins. Overall, this review emphasizes the fundamental roles of IQGAPs in coupling activated receptors to cellular homeostasis.

Figure 1.

IQGAP1 scaffolds signaling pathways upon activation of EGFR. IQGAP1 binds to EGFR, both directly and via the adaptor protein ShcA. EGF stimulates IQGAP1-mediated scaffolding of the PI3K/mTor/Akt and MAPK pathways, which activates Akt and ERK, respectively. IQGAP1 also facilitates EGF-stimulated activation of the transcription factors STAT1 and STAT3, and stabilizes the GTP-bound forms of the GTPases Cdc42, RhoA, and RhoC. The functional implications of IQGAP1-mediated signaling are indicated below each pathway. Ca²⁺/calmodulin (CaM), generated by EGF/EGFR-induced increase of cytosolic Ca²⁺, binds IQGAP1 and prevents its binding to EGFR, providing negative feedback. Green and red arrows represent stimulation and inhibition, respectively. The figure was generated in BioRender.

Figure 2.

IQGAP1 scaffolds signaling complexes at activated receptor tyrosine kinases. (A) VEGFR2: VEGFR2 activated by VEGF binds IQGAP1. IQGAP1 couples VEGF/VEGFR2 to (i) Raf activation and (ii) activation of the ROS-producing Nox2 oxidase by Rac1-GTP. (iii) ROS stimulate phosphorylation of VE-cadherin, which loosens cell adhesion. (iv) ROS also activate Akt and induce cysteine oxidation (Cys-OH) of IQGAP1. Cys-OH, active Akt, and active Raf drive cell migration and proliferation. (B) PDGFR-β: PDGFR-β activated by PDGF binds IQGAP1. (i) IQGAP1 stimulates PDGFR-β activation. (ii) IQGAP1 assembles at activated PDGFR-β a complex containing paxillin, vinculin, and focal adhesion kinase (FAK) that form integrin-mediated focal adhesion structures. (iii) IQGAP1 also recruits Rac1-GTP and the copper transporter ATP7A (during trafficking to the plasma membrane), which delivers Cu²⁺ to Cu²⁺-dependent enzymes. These events drive cell migration. ECM, extracellular matrix. (C) FGFR1: FGFR1 activated by FGF2 binds IQGAP1. (i) IQGAP1 recruits N-WASP and Arp2/3, which facilitates Arp2/3 activation by N-WASP (ii) to promote lamellipodium formation and cell migration. (D) Insulin receptor: IQGAP1 binds to IR and IRS-1, which (i) initiates the phosphorylation-dependent recruitment of PI3K to IRS-1 and facilitates Akt activation. (ii) Active Akt induces translocation of GLUT4 to the plasma membrane, enabling glucose entry into adipocytes and skeletal muscle cells. (iii) IQGAP1 also facilitates ERK activation by insulin. (iv) In the pancreas, IQGAP1 binding to the exocyst protein EXOC7 and septin SEPT2 promotes exocytic release of insulin. Green and red arrows represent stimulation and inhibition, respectively. The figure was generated in BioRender.

Figure 3.

IQGAP1 integrates GPCR signaling. (A) CXCR4: (i) SDF-1 induces recruitment of IQGAP1 to CXCR4-containing endosomes. (ii) By binding α-tubulin in microtubules, IQGAP1 coordinates post-endocytic trafficking of CXCR4. (iii) At the cell surface, IQGAP1 stimulates SDF-1/CXCR4-induced ERK activation to promote cell migration. (B) MOR1: (i) MOR1 activation by DAMGO increases the amount of IQGAP1 and stimulates active Rac1 and nuclear ERK. (ii) Morphine activates ERK and PKCα independently of IQGAP1. (C) ET-1Rs: (i) Stimulation of ET-1Rs by ET-1 increases the amount of IQGAP1 and induces IQGAP1 binding to β-arrestin1, and RacGAP1. This reduces active Rac1 and increases active RhoA and RhoC, which stimulates cell migration. (ii) The IQGAP1:β-arrestin1 complex also promotes invadopodium formation and degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs), thereby coordinating cell invasion. (D) LPA1: (i) IQGAP1 binds constitutively to Rap1A and β-arrestin2. (ii) LPA enhances binding of active Rap1A and IQGAP1 to LPA1. (iii) LPA also induces colocalization of β-arrestin2 and IQGAP1 at the leading edge of migrating cells, which increases cell migration and invasion. (E) LGR5: (i) IQGAP1 binding to overexpressed LGR5 reduces IQGAP1 phosphorylation, which increases its association with Rac1-GTP and actin. (ii) Because active Rac1 decreases IQGAP1:β-catenin interaction, this mechanism is suggested to promote the formation of the E-cadherin:β-catenin:α-catenin complex and to increase actin cross-linking. Green arrows represent stimulation, while dashed arrows depict speculative mechanisms not confirmed by experimental data. The figure was generated in BioRender.

Figure 4.

IQGAP1 participates in adhesion receptor signaling. (A) β1-integrin: IQGAP1 binds to β1-integrin, (i) together with the kinase CaMKII and the phosphatase PP2A, which assemble and disassemble the complex, respectively. (ii) Rac1 is inactivated by RacGAP1 in the complex, (iii) while RhoA and Arf6 are activated. (iv) These associations promote actin polymerization and influence β1-integrin trafficking. (B) β3-integrin: (i) IQGAP1 promotes membrane targeting of β3-integrin. (ii) At the plasma membrane, IQGAP1 interacts with β3-integrin, and the complex enhances cortical actin polymerization. (C) E-cadherin: (i) IQGAP1 binds both E-cadherin and β-catenin (β), which dissociates α-catenin (α) from adherens junctions, leading to loosened intercellular adhesion. (ii) Binding of calmodulin (CaM) or active Rac1/Cdc42 (only Rac1 shown) to IQGAP1 prevents its interaction with E-cadherin and β-catenin, thereby stabilizing E-cadherin:β-catenin:α-catenin complexes. Moreover, IQGAP1 bound to Rac1/Cdc42-GTP stimulates actin crosslinking at adherens junctions. (D) CD44: Hyaluronan (HA) initiates the formation of a CD44:IQGAP1 complex at the cell surface. (i) IQGAP1 scaffolds actin and active Cdc42 in the complex to stimulate cell migration. (ii) Downstream of HA/CD44, IQGAP1 activates ERK2 which, in turn, increases estrogen receptor (ER) and Elk1 transcriptional activities. Green and red arrows represent stimulation and inhibition, respectively. The figure was generated in BioRender.