A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin

Dubash, Adi D.; Wennerberg, Krister; Garcı́a-Mata, Rafael; Menold, Marisa M.; Arthur, William T.; Burridge, Keith

doi:10.1242/jcs.003806

Cited by 103 publications

(101 citation statements)

References 50 publications

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“…Arachidonic acid-treated cells exhibited short cortical actin stress fibers accompanied by actin arcs (supplemental Fig. S3, D-F), a type of actin cytoskeleton structure previously shown to correspond with Rho activity (19). Cell morphology and actin structure were similar in both non-transfected and HA-tagged wild-type RhoA-expressing cells (supplemental Fig.…”

Section: Resultsmentioning

confidence: 63%

“…Immunoprecipitations of HSP27 from cells that had been treated with arachidonic acid showed a significant increase in association with p115RhoGEF (Fig. 5B), a Rho guanine nucleotide exchange factor that regulates RhoA signaling (19,21,59). Because inhibition of p38 blocked RhoA activity, we asked whether the HSP27⅐p115RhoGEF association was dependent on p38 activation.…”

Section: Rock Is Necessary For Adhesion Of Mda-mb-435 Cells To Collagmentioning

confidence: 97%

“…6A). To determine whether p115RhoGEF is required for RhoA activation, we transfected cells with wild-type p115RhoGEF (FLp115-RhoGEF) or a dominant negative form (4Ap115RhoGEF) of p115RhoGEF (19). RhoA activity was induced by arachidonic acid in cells transfected with wild-type p115RhoGEF, but this activation was blocked in cells transfected with the dominant negative GEF (Fig.…”

Section: P38 Mapk and P115rhogef Are Required For Rhoa Activation Leamentioning

confidence: 99%

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Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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Rho GTPases are critical components of cellular signal transduction pathways. Both hyperactivity and overexpression of these proteins have been observed in human cancers and have been implicated as important factors in metastasis. We previously showed that dietary n-6 fatty acids increase cancer cell adhesion to extracellular matrix proteins, such as type IV collagen. Here we report that in MDA-MB-435 human melanoma cells, arachidonic acid activates RhoA, and inhibition of RhoA signaling with either C3 exoenzyme or dominant negative Rho blocked arachidonic acid-induced cell adhesion. Inhibition of the Rho kinase (ROCK) with either small molecule inhibitors or ROCK II-specific small interfering RNA (siRNA) blocked the fatty acid-induced adhesion. However, unlike other systems, inhibition of ROCK did not block the activation of p38 mitogenactivated protein kinase (MAPK); instead, Rho activation depended on p38 MAPK activity and the presence of heat shock protein 27 (HSP27), which is phosphorylated downstream of p38 after arachidonic acid treatment. HSP27 associated with p115RhoGEF in fatty acid-treated cells, and this association was blocked when p38 was inhibited. Furthermore, siRNA knockdown of HSP27 blocked the fatty acid-stimulated Rho activity. Expression of dominant negative p115-RhoGEF or p115RhoGEF-specific siRNA inhibited both RhoA activation and adhesion on type IV collagen, whereas a constitutively active p115RhoGEF restored the arachidonic acid stimulation in cells in which the p38 MAPK had been inhibited. These data suggest that n-6 dietary fatty acids stimulate a set of interactions that regulates cell adhesion through RhoA and ROCK II via a p38 MAPK-dependent association of HSP27 and p115RhoGEF.The ability of tumor cells to metastasize to secondary sites is a hallmark of neoplastic disease. Unfortunately, this propensity to spread is the primary cause of morbidity and death in cancer patients (1). Metastasis is clearly a highly regulated, multistep process that occurs in a spatiotemporal manner (2-4). To escape the restrictive compartment boundaries characteristic of adult tissue, separate intravasation and extravasation steps requiring alterations in co-adhesion, adhesion, invasion, and migration must occur. Execution of these biological processes, involving multiple proteins and cellular organelles, require highly coordinated cell signaling mechanisms.The Rho family of small GTPases regulates many facets of cytoskeletal rearrangements that facilitate cell attachment and migration (5-7). Rho GTPases act as molecular switches by changing from an inactive GDP-bound conformation to an active GTPbound conformation, thereby regulating a signaling pathway. These proteins are directly regulated by Rho guanine nucleotide exchange factors (GEFs), 2 Rho GTPase activating proteins, and Rho GDP-dissociation inhibitors (8 -12). RhoGEFs bind to the GTPase to catalyze the dissociation of GDP, allowing the binding of GTP and thereby promoting Rho activation (8). The RGS (regulators of G protein signaling) domain-c...

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Section: Resultsmentioning

confidence: 63%

Section: Rock Is Necessary For Adhesion Of Mda-mb-435 Cells To Collagmentioning

confidence: 97%

Section: P38 Mapk and P115rhogef Are Required For Rhoa Activation Leamentioning

confidence: 99%

See 1 more Smart Citation

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Garcia

Ray

Lackford

et al. 2009

Journal of Biological Chemistry

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“…Interestingly, a connection between Rab21, integrins and actomyosin regulation has been reported during cytokinesis (Pellinen et al, , 2008. This is probably through the activation of Rho-ROCK function as ligand-bound integrin a5 can signal to RhoGEFs and thereby increase Rho activity (Ren et al, 1999;Dubash et al, 2007;Huveneers et al, 2008). Integrin a5 has also been implicated in collagen gel contraction in other fibroblast types (Liu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

2009

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BACKGROUND: Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion. METHODS: We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC). RESULTS: We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs. CONCLUSIONS: Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin a5 at the plasma membrane and subsequent force-mediated matrix remodelling.

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“…Indeed, reported GEF activity is toward RhoA or Rac1 for FARP1 30,31 and toward Rho isoforms for ARHGEF1. [32][33][34] The GEF activity is mediated by the Dbl homology domain (DH domain) and an extensive analysis of the DH domain of Rho-GEFs combined to their biochemical properties on Rho GTPases predicts that FARP1 may have a nucleotide exchange activity toward Cdc42. 35 The relationship between ARHGEF1 and Rac1 is more puzzling.…”

Section: Down-regulation Of Rho Gtpases and Tumorigenesismentioning

confidence: 99%

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

et al. 2016

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Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes. In contrast, we have recently reported that decreased activities of Cdc42 and Rac1 as well as decreased expression of 2 Rho-GEFs, FARP1 and ARHGEF1, correlate with pheochromocytomas, a tumor developing in the medulla of the adrenal gland (Croise et al., Endocrine Related Cancer, 2016). Here we highlight the major evidence and further study the correlation between Rho GTPases activities and expression levels of ARHGEF1 and FARP1. Finally we also discuss how the decrease of Cdc42 and Rac1 activities may help human pheochromocytomas to develop and comment the possible relationship between FARP1, ARHGEF1 and the 2 Rho GTPases Cdc42 and Rac1 in tumorigenesis.

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A novel role for Lsc/p115 RhoGEF and LARG in regulating RhoA activity downstream of adhesion to fibronectin

Cited by 103 publications

References 50 publications

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

Arachidonic Acid Stimulates Cell Adhesion through a Novel p38 MAPK-RhoA Signaling Pathway That Involves Heat Shock Protein 27

A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor

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