IQGAP1: a key regulator of adhesion and migration

Noritake, Jun; Watanabe, Takashi; Sato, Kazumasa; Wang, Shujie; Kaibuchi, Kozo

doi:10.1242/jcs.02379

Cited by 334 publications

(348 citation statements)

References 78 publications

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“…Of the many putative proteins identified (Table S1), two candidates, IQGAP1 and IQGAP3, were particularly notable for their pleiotropic roles in signal transduction (35,36). The three highly homologous IQGAPs (IQGAP1-3) contain multiple domains that bind to and modulate the activity of a plethora of signaling molecules, including Rho GTPases, MAP kinase (MAPK), and components of Wnt pathway E-cadherin, β-catenin, and adenomatous polyposis coli (35,36). We first confirmed that full-length LGR4 interacts with IQGAP1 as well as with IQGAP2 and IQGAP3 by co-IP analysis ( Fig.…”

Section: Rspo-mentioning

confidence: 99%

“…IQGAPs contain several domains that bind to distinct signaling and structural proteins (35,36). To map the IQGAP1 domain responsible for interacting with LGR4, a series of IQGAP1 truncation and deletion mutants were constructed (Fig.…”

Section: Rspo-mentioning

confidence: 99%

“…This pathway regulates cell polarity and migration through modulating activities of the Rho family of GTPases (Rho, Rac, and CDC42), which all interact with IQGAPs directly (35,36,42). Importantly, IQGAP1 can recruit the actin assembly proteins neural Wiskott-Aldrich syndrome protein (N-WASP) and mDia1 to coordinate receptor activation with FA assembly, which is critical to the control of cell adhesion and migration (43)(44)(45).…”

Section: Rspo-mentioning

confidence: 99%

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RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

Carmon

Gong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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R-spondins (RSPOs) and their receptor leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4) play pleiotropic roles in normal and cancer development as well as the survival of adult stem cells through potentiation of Wnt signaling. Current evidence indicates that RSPO-LGR4 functions to elevate levels of Wnt receptors through direct inhibition of two membrane-bound E3 ligases (RNF43 and ZNRF3), which otherwise ubiquitinate Wnt receptors for degradation. Whether RSPO-LGR4 is coupled to intracellular signaling proteins to regulate Wnt pathways remains unknown. We identified the intracellular scaffold protein IQ motif containing GTPase-activating protein 1 (IQGAP1) as an LGR4-interacting protein that mediates RSPO-LGR4's interaction with the Wnt signalosome. IQGAP1 binds to and modulates the activities of a plethora of signaling molecules, including MAP kinases, Rho GTPases, and components of the Wnt signaling pathways. Interaction of LGR4 with IQGAP1 brings RSPO-LGR4 to the Wnt signaling complex through enhanced IQGAP1-DVL interaction following RSPO stimulation. In this configuration, RSPO-LGR4-IQGAP1 potentiates β-catenin-dependent signaling by promoting MEK1/2-medidated phosphorylation of LRP5/6 as well as β-catenin-independent signaling through regulation of actin dynamics. Overall, these findings reveal that RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex, leading to potent and robust potentiation of both the canonical and noncanonical pathways of Wnt signaling.cell signaling | receptor activation | adhesion | migration T he four R-spondins (RSPO1-4) and three related leucinerich repeat-containing G-protein coupled receptors, LGR4, LGR5, and LGR6 (LGR4-6), constitute a ligand-receptor system that plays critical roles in development, stem cell survival, and oncogenesis (1-6). Mutations of RSPO1 and RSPO4 affect sex development and nail formation (7-9), respectively, and haplotype insufficiency of LGR4 in humans is associated with several diseases and other traits (10). In the mouse, knockouts of LGR4 or RSPOs are presented with severe developmental abnormalities, including neonatal/embryonic lethality accompanied by hypoplasia and defects in tubule elongation and branching in the kidney, lung, mammary gland, and testis (11-16).LGR5 and LGR6 are markers of adult stem cells in the intestine and other select solid tissues (2).LGR4 is frequently coexpressed with LGR5 or LGR6 and is required for the survival of crypt stem cells in the gut (4, 17). Recurrent, gain-of-expression gene fusions of RSPO2 (to EIF3E) and RSPO3 (to PTPRK) occur in a subset of colorectal cancers (18). In mouse mammary tumor virus-induced mouse models of breast and colon cancer, RSPO2 and RSPO3 were identified as two of the most commonly activated alleles (19-21). Ectopic expression of RSPO2/3 in mouse mammary epithelial cells led to an increase in invasiveness in vitro and in tumor formation and metastasis in vivo (20,22). LGR4 is up-reg...

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Section: Rspo-mentioning

confidence: 99%

Section: Rspo-mentioning

confidence: 99%

Section: Rspo-mentioning

confidence: 99%

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RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

Carmon

Gong

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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“…IQGAP1 has been reported to interact with βArr2, a scaffold protein that binds to activated GPCRs and regulates signaling and receptor endocytosis (20). IQGAP1 promotes proliferation and migration, and overexpression has been associated with poor prog-nosis in advanced colorectal cancer (21)(22)(23). Interestingly, IQGAP1 can coordinate cell growth and division in a phosphorylation-dependent manner (24).…”

Section: Gpr161 Induces Migration and Invasion Of Mammary Epithelial mentioning

confidence: 99%

G-protein–coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion

Feigin

Xue

Hammell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Recent advances in DNA sequencing and bioinformatics tools have allowed the large-scale characterization of genetic alterations in human tumors. We exploited genomics data to identify commonly occurring alterations in G-protein–coupled receptors (GPCRs) in triple-negative breast cancer (TNBC), a subset of breast cancer with poor prognosis and lacking effective targeted therapy. We have discovered that the orphan GPCR, G-protein–coupled receptor 161 ( GPR161 ), is overexpressed specifically in TNBC and correlates with poor prognosis. We identify GPR161 as a regulator of mammary epithelial cell proliferation and invasion in a mammalian target of rapamycin signaling-pathway–dependent manner. Down-regulation of GPR161 in a TNBC-derived cell line impairs cell growth, suggesting that GPR161 is a drug target for breast cancer.

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“…27 CLIP1 also interacts with IQGAP1 (IQ Motif Containing GTPase Activating Protein 1), which together with CLIP1, is part of a complex that has a role in linking the actin cytoskeleton to MTs during cell migration. 28 In rat neurons, CLIP1 together with IQGAP1 controls dendrite morphology, again possibly by regulating the interaction between MTs and the actin cytoskeleton. 9 The second zinc knuckle in the C-terminal domain of CLIP1 takes part in direct interaction with the dynactin subunit 1, DCTN1 (P150 Glued ) of the dynein/dynactin complex.…”

Section: Discussionmentioning

confidence: 99%

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

Larti¹,

Kahrizi²,

Musante³

et al. 2014

Eur J Hum Genet

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In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score ¼ 3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which specifically associates with the ends of growing MTs. These proteins regulate MT dynamic behavior and are important for MT-mediated transport over the length of axons and dendrites. As such, CLIP1 may have a role in neuronal development. We studied lymphoblastoid and skin fibroblast cell lines established from healthy and affected patients. RT-PCR and western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Furthermore, immunofluorescence analyses showed MT plus-end staining only in fibroblasts containing the wild-type (and not the mutant) CLIP1 protein. Collectively, our data suggest that defects in CLIP1 may lead to ARID.

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IQGAP1: a key regulator of adhesion and migration

Cited by 334 publications

References 78 publications

RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

RSPO–LGR4 functions via IQGAP1 to potentiate Wnt signaling

G-protein–coupled receptor GPR161 is overexpressed in breast cancer and is a promoter of cell proliferation and invasion

A defect in the CLIP1 gene (CLIP-170) can cause autosomal recessive intellectual disability

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