Rho Isoform-specific Interaction with IQGAP1 Promotes Breast Cancer Cell Proliferation and Migration

Casteel, Darren E.; Turner, Stephanie; Schwappacher, Raphaela; Rangaswami, Hema; Su-Yuo, Jacqueline; Zhuang, Shunhui; Boss, Gerry R.; Pilz, Renate B.

doi:10.1074/jbc.m112.377499

Cited by 56 publications

(66 citation statements)

References 47 publications

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“…Consistent with our model, others have reported that IQGAP1 binds preferentially to GTP-Rac1 (Kuroda et al, 1996), suggesting that IQGAP1 might immobilise active Rac1 at sites of integrin activation and subsequently recruit RacGAP1 to promote GTP hydrolysis. Consistent with IQGAP1 suppressing Rac1 activity, a recent study reported that IQGAP1 promoted RhoA activation (Casteel et al, 2012), a well-established antagonist of Rac1 activity (Guilluy et al, 2011). Proteomic analyses of IQGAP1-associated proteins identified a putative RhoA GEF, namely pleckstrin homology domain-containing family G member 3, which could be involved in IQGAP1-mediated activation of RhoA (Fig.…”

Section: Discussionmentioning

confidence: 66%

“…Accumulating evidence indicates that IQGAP1 can function to regulate the activity of small GTPases both positively and negatively (Bashour et al, 1997;Casteel et al, 2012;Jeong et al, 2007). To date, studies of IQGAP1-dependent Rac1 activity modulation have focused primarily on the response triggered by growth factors or cytokines (Brown and Sacks, 2006;David et al, 2011;Hu et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

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Rac1 is deactivated at integrin activation sites via an IQGAP1/filamin-A/RacGAP1 pathway

Jacquemet

Morgan

Byron

et al. 2013

Journal of Cell Science

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SummaryCell migration makes a fundamental contribution to both normal physiology and disease pathogenesis. Integrin engagement with extracellular ligands spatially controls, via the cyclical activation and deactivation of the small GTPase Rac1, the dynamic membrane protrusion and cytoskeletal reorganization events that are required for directional migration. Although the pathways that control integrinmediated Rac1 activation are reasonably well defined, the mechanisms that are responsible for switching off activity are poorly understood. Here, proteomic analysis of activated integrin-associated complexes suggests filamin-A and IQ-motif-containing GTPase-activating protein 1 (IQGAP1) as candidates that link b1 integrin to Rac1. siRNA-mediated knockdown of either filamin-A or IQGAP1 induced high, dysregulated Rac1 activity during cell spreading on fibronectin. Using immunoprecipitation and immunocytochemistry, filamin-A and IQGAP1 were shown to be part of a complex that is recruited to active b1 integrin. Mass spectrometric analysis of individual filamin-A, IQGAP1 and Rac1 pull-downs and biochemical analysis, identified RacGAP1 as a novel IQGAP1 binding partner. Further immunoprecipitation and immunocytochemistry analyses demonstrated that RacGAP1 is recruited to IQGAP1 and active b1 integrin, and that suppression of RacGAP1 expression triggered elevated Rac1 activity during spreading on fibronectin. Consistent with these findings, reduced expression of filamin-A, IQGAP1 or RacGAP1 triggered unconstrained membrane protrusion and disrupted directional cell migration on fibrillar extracellular matrices. These findings suggest a model whereby integrin engagement, followed by filamin-A, IQGAP1 and RacGAP1 recruitment, deactivates Rac1 to constrain its activity spatially and thereby coordinate directional cell migration.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Rac1 is deactivated at integrin activation sites via an IQGAP1/filamin-A/RacGAP1 pathway

Jacquemet

Morgan

Byron

et al. 2013

Journal of Cell Science

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“…The function of IQGAP1 protein includes cytoskeltal regulation, coordinating cadeherin mediated cell-cell adhesion, cell polarization and actin reorganization to promote cell migration. Accumulating evidence strongly supports IQGAP1 is an oncogene (Casteel et al, 2012;White et al, 2012). A comparison of structure and function of IQGAP2 with those of IQGAP1 reveals some similarities and several differences.…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of IQGAP1/2 in Hepatocellular Carcinoma and its Relationship with Clinical Outcomes

Xia¹,

Wang²,

Chen³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…IQGAP1 does not possess GTPase activating activity (7). However, one of its demonstrated properties is that it binds Rho family GTPases, including RhoA (8,9). We therefore considered the possibility that IQGAP1 determines RhoA-dependent airway smooth muscle contractility.…”

Section: Introductionmentioning

confidence: 99%

IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction

Bhattacharya¹,

Sundaram²,

Kudo³

et al. 2014

J. Clin. Invest.

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Rho Isoform-specific Interaction with IQGAP1 Promotes Breast Cancer Cell Proliferation and Migration

Cited by 56 publications

References 47 publications

Rac1 is deactivated at integrin activation sites via an IQGAP1/filamin-A/RacGAP1 pathway

Rac1 is deactivated at integrin activation sites via an IQGAP1/filamin-A/RacGAP1 pathway

Differential Expression of IQGAP1/2 in Hepatocellular Carcinoma and its Relationship with Clinical Outcomes

IQGAP1-dependent scaffold suppresses RhoA and inhibits airway smooth muscle contraction

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