Coordination of Rho and Rac GTPase Function via p190B RhoGAP

Bustos, Rodrigo I.; Forget, Marie-Annick; Settleman, Jeffrey; Hansen, Steen Ingemann

doi:10.1016/j.cub.2008.09.019

Cited by 78 publications

(87 citation statements)

References 26 publications

(34 reference statements)

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“…However for the same influence diagram (Fig. 1a), experimental evidence suggest that Rac1 can inhibit RhoA by either (1) inhibiting RhoA-GEFs (p115 46 and GEF-H1 33,44,47 ) or (2) activating a RhoA-GAP (p190RhoGAP) 31,48 . Our analysis so far considered the first possible mechanism of GEF-mediated inhibition.…”

Section: An Alternative Model Of Rac1 Mediated Activation Of Rhoa-gapmentioning

confidence: 87%

Control of the G-protein cascade dynamics by GDP dissociation inhibitors

et al. 2013

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A network of the Rho family GTPases, which cycle between an inactive GDP-bound and active GTP-bound states, controls key cellular processes, including proliferation and migration. Activating and deactivating GTPase transitions are controlled by guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and GDP dissociation inhibitors (GDIs) that sequester GTPases from the membrane to the cytoplasm. Here we show that a cascade of two Rho family GTPases, RhoA and Rac1, regulated by RhoGDI1, exhibits distinct modes of the dynamic behavior, including abrupt, bistable switches, excitable overshoot transitions and oscillations. The RhoGDI1 abundance and signal-induced changes in the RhoGDI1 affinity for GTPases control these different dynamics, enabling transitions from a single stable steady state to bistability, to excitable pulses and to sustained oscillations of GTPase activities. These RhoGDI1-controlled dynamic modes of RhoA and Rac1 activities form the basis of cell migration behaviors, including protrusionretraction cycles at the leading edge of migrating cells.2

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Section: An Alternative Model Of Rac1 Mediated Activation Of Rhoa-gapmentioning

confidence: 87%

Control of the G-protein cascade dynamics by GDP dissociation inhibitors

et al. 2013

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“…This counter activity of Rac and Rho, observed in multiple systems, is key to cell migration and, therefore, may be necessary for tumor cell metastasis (60 -63). The cross-talk regulating the counter activity of Rho and Rac remains unclear (64 -66), although recent work suggests that proteins Rho GTPase-activating proteins may be involved (67). The various Rho isoforms have been shown to play a role in tumor metastasis, with RhoC being most frequently associated with malignant phenotypes (46).…”

Section: Discussionmentioning

confidence: 99%

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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“…shown to mutually antagonized each other at the front and back (Bustos et al, 2008;Ohta et al, 2006) Figure. …”

Section: Establishment Of Cell Polaritymentioning

confidence: 96%