Bacterial protein toxins targeting Rho GTPases

Lerm, Maria; Schmidt, Gudula; Aktories, Klaus

doi:10.1111/j.1574-6968.2000.tb09159.x

Cited by 85 publications

(36 citation statements)

References 46 publications

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“…This approach has been employed before as an indication of partial release of RhoA by RhoGDI following incubation of the RhoA-RhoGDI complex with phosphoinositides (30). The C3 exotransferase is a bacterial toxin that ADP-ribosylates RhoA on Asn-41 (48) and results in RhoA inactivation through enhanced interaction with RhoGDI (49). When purified RhoA-RhoGDI complexes were incubated with TAT-C3, little ADP-ribosylation occurred either in the presence or absence of PtdIns(4,5)P 2 .…”

Section: Resultsmentioning

confidence: 99%

Serine 34 Phosphorylation of Rho Guanine Dissociation Inhibitor (RhoGDIα) Links Signaling from Conventional Protein Kinase C to RhoGTPase in Cell Adhesion

Dovas

Choi

Yoneda

et al. 2010

Journal of Biological Chemistry

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Conventional protein kinase C (PKC) isoforms are essential serine/threonine kinases regulating many signaling networks. At cell adhesion sites, PKCα can impact the actin cytoskeleton through its influence on RhoGTPases, but the intermediate steps are not well known. One important regulator of RhoGTPase function is the multifunctional guanine nucleotide dissociation inhibitor RhoGDIα that sequesters several related RhoGTPases in an inactive form, but it may also target them through interactions with actin-associated proteins. Here, it is demonstrated that conventional PKC phosphorylates RhoGDIα on serine 34, resulting in a specific decrease in affinity for RhoA but not Rac1 or Cdc42. The mechanism of RhoGDIα phosphorylation is distinct, requiring the kinase and phosphatidylinositol 4,5-bisphosphate, consistent with recent evidence that the inositide can activate, localize, and orient PKCα in membranes. Phosphospecific antibodies reveal endogenous phosphorylation in several cell types that is sensitive to adhesion events triggered, for example, by hepatocyte growth factor. Phosphorylation is also sensitive to PKC inhibition. Together with fluorescence resonance energy transfer microscopy sensing GTP-RhoA levels, the data reveal a common pathway in cell adhesion linking two essential mediators, conventional PKC and RhoA.

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Section: Resultsmentioning

confidence: 99%

Serine 34 Phosphorylation of Rho Guanine Dissociation Inhibitor (RhoGDIα) Links Signaling from Conventional Protein Kinase C to RhoGTPase in Cell Adhesion

Dovas

Choi

Yoneda

et al. 2010

Journal of Biological Chemistry

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“…These include, among others, dominant negative mutants [5], and chemicals and toxins to covalently modify Rho proteins. Deamination of the proteins result in activation while ribosylation or glucosylation can inactivate them [6,7]. Since naturally occurring mutants of RhoGTPases have not been described, there is some doubts about the applicability of research using mutants.…”

Section: Rho and Nfκb (Nuclear Factor κB): Key Cellular Regulatorsmentioning

confidence: 99%

Rho protein GTPases and their interactions with NFκB: crossroads of inflammation and matrix biology

2014

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The RhoGTPases, with RhoA, Cdc42 and Rac being major members, are a group of key ubiquitous proteins present in all eukaryotic organisms that subserve such important functions as cell migration, adhesion and differentiation. The NFκB (nuclear factor κB) is a family of constitutive and inducible transcription factors that through their diverse target genes, play a major role in processes such as cytokine expression, stress regulation, cell division and transformation. Research over the past decade has uncovered new molecular links between the RhoGTPases and the NFκB pathway, with the RhoGTPases playing a positive or negative regulatory role on NFκB activation depending on the context. The RhoA–NFκB interaction has been shown to be important in cytokine-activated NFκB processes, such as those induced by TNFα (tumour necrosis factor α). On the other hand, Rac is important for activating the NFκB response downstream of integrin activation, such as after phagocytosis. Specific residues of Rac1 are important for triggering NFκB activation, and mutations do obliterate this response. Other upstream triggers of the RhoGTPase–NFκB interactions include the suppressive p120 catenin, with implications for skin inflammation. The networks described here are not only important areas for further research, but are also significant for discovery of targets for translational medicine.

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“…However, these inhibitors may nonspecifically deactivate other members of the Rho subfamily such as RhoB/C, Rac1, or CDC42. Additionally, it is also unclear as to the completeness of this RhoA disruption [13]. To address these issues, Pleines, et al, have generated transgenic mice with megakaryocyte/platelet-specific deletion of RhoA [8].…”

Section: Introductionmentioning

confidence: 99%

RhoA Is Essential for Maintaining Normal Megakaryocyte Ploidy and Platelet Generation

et al. 2013

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RhoA plays a multifaceted role in platelet biology. During platelet development, RhoA has been proposed to regulate endomitosis, proplatelet formation, and platelet release, in addition to having a role in platelet activation. These processes were previously studied using pharmacological inhibitors in vitro, which have potential drawbacks, such as non-specific inhibition or incomplete disruption of the intended target proteins. Therefore, we developed a conditional knockout mouse model utilizing the CRE-LOX strategy to ablate RhoA, specifically in megakaryocytes and in platelets to determine its role in platelet development. We demonstrated that deleting RhoA in megakaryocytes in vivo resulted in significant macrothrombocytopenia. RhoA-null megakaryocytes were larger, had higher mean ploidy, and exhibited stiff membranes with micropipette aspiration. However, in contrast to the results observed in experiments relying upon pharmacologic inhibitors, we did not observe any defects in proplatelet formation in megakaryocytes lacking RhoA. Infused RhoA-null megakaryocytes rapidly released platelets, but platelet levels rapidly plummeted within several hours. Our evidence supports the hypothesis that changes in membrane rheology caused infused RhoA-null megakaryocytes to prematurely release aberrant platelets that were unstable. These platelets were cleared quickly from circulation, which led to the macrothrombocytopenia. These observations demonstrate that RhoA is critical for maintaining normal megakaryocyte development and the production of normal platelets.

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Bacterial protein toxins targeting Rho GTPases

Cited by 85 publications

References 46 publications

Serine 34 Phosphorylation of Rho Guanine Dissociation Inhibitor (RhoGDIα) Links Signaling from Conventional Protein Kinase C to RhoGTPase in Cell Adhesion

Serine 34 Phosphorylation of Rho Guanine Dissociation Inhibitor (RhoGDIα) Links Signaling from Conventional Protein Kinase C to RhoGTPase in Cell Adhesion

Rho protein GTPases and their interactions with NFκB: crossroads of inflammation and matrix biology

RhoA Is Essential for Maintaining Normal Megakaryocyte Ploidy and Platelet Generation

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