IQGAP1 Interaction with RHO Family Proteins Revisited

Nouri, Kazem; Fansa, Eyad K.; Amin, Ehsan; Dvorský, Radovan; Gremer, Lothar; Willbold, Dieter; Schmitt, Lutz; Timson, David J.; Ahmadian, Mohammad Réza

doi:10.1074/jbc.m116.752121

Cited by 27 publications

(15 citation statements)

References 77 publications

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“…Binding of Rac1/CDC42 to IQGAP1 is regulated by phosphorylation of IQGAP1 at two sites (Ser-1441 and -1443) ( 25 , 26 , 41 ). Detailed kinetic analysis showed that phosphorylation at Ser-1443 led to a decrease in the affinity of human IQGAP1 for Rac1 and CDC42 ( 27 ). To test whether LGR5 regulates IQGAP1–Rac1 interaction through modulation of IQGAP1 phosphorylation, we probed the level of phospho-IQGAP1 with an anti-phosphoserine antibody (no antibody specifically against Ser-1441 or Ser-1443 of IQGAP1 is available ( 42 )).…”

Section: Resultsmentioning

confidence: 99%

“…Initially, we found that overexpression of LGR5 consistently led to increased binding of Rac1 and actin to IQGAP1 in co-IP analysis. Because it was reported that binding of Rac1/CDC42 to IQGAP1 is inhibited by phosphorylation at Ser-1441/1443 of IQGAP1 ( 26 , 27 , 41 ), we asked whether LGR5 modulates phosphorylation of IQGAP1 at these sites to regulate IQGAP1–Rac1 interaction. Indeed, LGR5 overexpression and KD of LGR5 led to a significant decrease and increase in Ser-1441/1443 phosphorylation, respectively, and LGR5 had no effect on PMA-induced phosphorylation of IQGAP1.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, binding of Rac1/CDC42 to IQGAP1 inhibits the IQGAP1–β-catenin interaction, leading to an increase in membrane-bound β-catenin, cell–cell adhesion, and F-actin cross-linking ( 20 , 24 ). Rac1/CDC42 binding to IQGAP1 is inhibited by phosphorylation at two serine sites (Ser-1441 and Ser-1443) of IQGAP1 ( 25 – 27 ). Here, we show that LGR5 interacts with IQGAP1 and decreases phosphorylation at these two serine sites, leading to increased binding of Rac1 and consequently enhancement of cell–cell adhesion.…”

Section: Introductionmentioning

confidence: 99%

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LGR5 receptor promotes cell–cell adhesion in stem cells and colon cancer cells via the IQGAP1–Rac1 pathway

Carmon

Gong

et al. 2017

Journal of Biological Chemistry

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Leucine-rich repeat-containing G protein–coupled receptor 5 (LGR5) is a bona fide marker of adult stem cells in several epithelial tissues, most notably in the intestinal crypts, and is highly up-regulated in many colorectal, hepatocellular, and ovarian cancers. LGR5 activation by R-spondin (RSPO) ligands potentiates Wnt/β-catenin signaling in vitro; however, deletion of LGR5 in stem cells has little or no effect on Wnt/β-catenin signaling or cell proliferation in vivo. Remarkably, modulation of LGR5 expression has a major impact on the actin cytoskeletal structure and cell adhesion in the absence of RSPO stimulation, but the molecular mechanism is unclear. Here, we show that LGR5 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1), an effector of Rac1/CDC42 GTPases, in the regulation of actin cytoskeleton dynamics and cell–cell adhesion. Specifically, LGR5 decreased levels of IQGAP1 phosphorylation at Ser-1441/1443, leading to increased binding of Rac1 to IQGAP1 and thus higher levels of cortical F-actin and enhanced cell–cell adhesion. LGR5 ablation in colon cancer cells and crypt stem cells resulted in loss of cortical F-actin, reduced cell–cell adhesion, and disrupted localization of adhesion-associated proteins. No evidence of LGR5 coupling to any of the four major subtypes of heterotrimeric G proteins was found. These findings suggest that LGR5 primarily functions via the IQGAP1–Rac1 pathway to strengthen cell–cell adhesion in normal adult crypt stem cells and colon cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LGR5 receptor promotes cell–cell adhesion in stem cells and colon cancer cells via the IQGAP1–Rac1 pathway

Carmon

Gong

et al. 2017

Journal of Biological Chemistry

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“…Reports point to interaction between Rho family small GTPases with IQGAP1 C-terminal domains which could regulate Rho kinase-myosin II dependent retraction. Rho inhibitors disrupt the WRAMP complex in human melanoma cells [ 17 ] and IQGAP1 is known to interact with RhoA [ 43 , 44 ]. While promoting activity of RhoA, IQGAP1 may also decrease activity of Rac1 [ 45 ] in the cell tail during melanoma migration, which may require interactions with C-terminal domains of IQGAP1.…”

Section: Discussionmentioning

confidence: 99%

Ras GAP-related and C-terminal domain-dependent localization and tumorigenic activities of IQGAP1 in melanoma cells

et al. 2017

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IQGAP1 interacts with a number of binding partners through a calponin homology domain (CHD), a WW motif, IQ repeats, a Ras GAP-related domain (GRD), and a conserved C-terminal (CT) domain. Among various biological and cellular functions, IQGAP1 is known to play a role in actin cytoskeleton dynamics during membrane ruffling and lamellipodium protrusion. In addition, phosphorylation near the CT domain is thought to control IQGAP1 activity through regulation of intramolecular interaction. In a previous study, we discovered that IQGAP1 preferentially localizes to retracting areas in B16F10 mouse melanoma cells, not areas of membrane ruffling and lamellipodium protrusion. Nothing is known of the domains needed for retraction localization and very little is known of IQGAP1 function in the actin cytoskeleton of melanoma cells. Thus, we examined localization of IQGAP1 mutants to retracting areas, and characterized knock down phenotypes on tissue culture plastic and physiologic-stiffness hydrogels. Localization of IQGAP1 mutants (S1441E/S1443D, S1441A/S1443A, ΔCHD, ΔGRD or ΔCT) to retracting and protruding cell edges were measured. In retracting areas there was a decrease in S1441A/S1443A, ΔGRD and ΔCT localization, a minor decrease in ΔCHD localization, and normal localization of the S1441E/S1443D mutant. In areas of cell protrusion just behind the lamellipodium leading edge, we surprisingly observed both ΔGRD and ΔCT localization, and increased number of microtubules. IQGAP1 knock down caused loss of cell polarity on laminin-coated glass, decreased proliferation on tissue culture polystyrene, and abnormal spheroid growth on laminin-coated hydrogels. We propose that the GRD and CT domains regulate IQGAP1 localization to retracting actin networks to promote a tumorigenic role in melanoma cells.

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“…As an example, IQGAP proteins have been described as a scaffolding platform that assemble small GTPases, GEFs, and effectors. This association is a multi-step process that involves a high affinity binding of IQGAP1 to the switch regions of the small G-protein (a GTP-dependent event), and low affinity binding to an adjacent region (16). The described direct association of IQGAP1 with the Rac-GEF Tiam1 and Rac1 exemplifies the relevance of multiprotein complexes in Rac1 activation (17).…”

Section: Regulation Of Rac Activity: Nucleotide Binding Post-translamentioning

confidence: 99%

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

Casado‐Medrano

Baker

López‐Haber

et al. 2018

Biochemical Society Transactions

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The family of Rho GTPases are involved in the dynamic control of cytoskeleton reorganization and other fundamental cellular functions, including growth, motility, and survival. Rac1, one of the best characterized Rho GTPases, is an established effector of receptors and an important node in signaling networks crucial for tumorigenesis and metastasis. Rac1 hyperactivation is common in human cancer, and could be the consequence of overexpression, abnormal upstream inputs, deregulated degradation, and/or anomalous intracellular localization. More recently, cancer associated gain-of-function mutations in Rac1 have been identified which contribute to tumor phenotypes and confer resistance to targeted therapies. Deregulated expression/activity of Rac Guanine nucleotide Exchange Factors (GEFs) responsible for Rac activation has been largely associated to a metastatic phenotype and drug resistance. Translating our extensive knowledge in Rac pathway biochemistry into a clinical setting still remains a major challenge, nonetheless remarkable opportunities for cancer therapeutics arise from promising lead compounds targeting Rac and its effectors.

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IQGAP1 Interaction with RHO Family Proteins Revisited

Cited by 27 publications

References 77 publications

LGR5 receptor promotes cell–cell adhesion in stem cells and colon cancer cells via the IQGAP1–Rac1 pathway

LGR5 receptor promotes cell–cell adhesion in stem cells and colon cancer cells via the IQGAP1–Rac1 pathway

Ras GAP-related and C-terminal domain-dependent localization and tumorigenic activities of IQGAP1 in melanoma cells

The role of Rac in tumor susceptibility and disease progression: from biochemistry to the clinic

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