Phosphorylation-mediated regulation of GEFs for RhoA

Patel, Maulik; Karginov, Andrei V.

doi:10.4161/cam.28058

Cited by 28 publications

(21 citation statements)

References 84 publications

(109 reference statements)

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“…Therefore, the RhoGEF activity of ARHGEF3 may be very low under normal conditions due to its nuclear sequestration, and it is switched on when specific conditions induce ARHGEF3 export from the nucleus. Post-translational modifications such as phosphorylation may also regulate RhoGEF activity of ARHGEF3, as reported for other RhoGEFs (Patel and Karginov, 2014). It will be of great importance for future studies to probe these mechanistic questions in order to elaborate therapeutic strategies targeting ARHGEF3.…”

Section: Discussionmentioning

confidence: 86%

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

You

Singh

Reyes-Ordoñez

et al. 2020

Preprint

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Skeletal muscle regeneration is essential for restoring muscle function upon injury and for the maintenance of muscle health with aging. ARHGEF3, a Rho-specific GEF, negatively regulates myoblast differentiation via mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling in a GEF-independent manner in vitro. Here, we investigated ARHGEF3's role in skeletal muscle regeneration by creating ARHGEF3 KO mice. These mice exhibited no discernible phenotype under normal conditions. Upon injury, however, ARHGEF3 deficiency enhanced the mass, fiber size and function of regenerating muscles in both young and aged mice. Surprisingly, these effects were not mediated by mTORC2-Akt signaling, but by the GEF activity of ARHGEF3. Furthermore, ARHGEF3 KO promoted muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength.Accordingly, in old mice, ARHGEF3 depletion prevented muscle weakness by restoring autophagy flux. Collectively, our findings identify an unexpected link between ARHGEF3 and autophagy-related muscle pathophysiology.

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Section: Discussionmentioning

confidence: 86%

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

You

Singh

Reyes-Ordoñez

et al. 2020

Preprint

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“…Besides, RhoA, as other small GTPases, can also be kept in an inactive state by guanine nucleotide dissociation inhibitors (GDIs) 79 . We observed that the action of CyaA provoked alterations of the phosphorylation state of several members of the GEF protein family, some of which were previously shown to directly promote RhoA activity 80 . For example, the protein known as Solo (or ARHGEF40) was shown to specifically induce RhoA activity in vascular endothelial cells 81 .…”

Section: Discussionmentioning

confidence: 80%

Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells

Novák

Fabrik

Linhartová

et al. 2017

Sci Rep

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The adenylate cyclase toxin (CyaA) of the whooping cough agent Bordetella pertussis subverts immune functions of host myeloid cells expressing the αMβ2 integrin (CD11b/CD18, CR3 or Mac-1). CyaA delivers into cytosol of cells an extremely catalytically active adenylyl cyclase enzyme, which disrupts the innate and adaptive immune functions of phagocytes through unregulated production of the key signaling molecule cAMP. We have used phosphoproteomics to analyze cAMP signaling of CyaA in murine bone marrow-derived dendritic cells. CyaA action resulted in alterations of phosphorylation state of a number of proteins that regulate actin cytoskeleton homeostasis, including Mena, Talin-1 and VASP. CyaA action repressed mTOR signaling through activation of mTORC1 inhibitors TSC2 and PRAS40 and altered phosphorylation of multiple chromatin remodelers, including the class II histone deacetylase HDAC5. CyaA toxin action further elicited inhibitory phosphorylation of SIK family kinases involved in modulation of immune response and provoked dephosphorylation of the transcriptional coactivator CRTC3, indicating that CyaA-promoted nuclear translocation of CRTC3 may account for CyaA-induced IL-10 production. These findings document the complexity of subversive physiological manipulation of myeloid phagocytes by the CyaA toxin, serving in immune evasion of the pertussis agent.

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“…The model was then ‘cleaned’ by independent verification or rejection of proteins/interactions from studying the original papers cited in [ 32 , 49 , 65 ], rejecting interactions which give implausible output data following simulations, and omitting some proteins whose functions in the EGFR pathway are ambiguous and superfluous to model outputs. Reactions involving RhoA which were not included in [ 65 ] (such as activation by the known Rho/Rac GEF Vav2) were included based on literature evidence [ 31 ] and the necessity of full incorporation of RhoA.…”

Section: Methodsmentioning

confidence: 99%

“…Given that RhoA and Rac1 are contained in a highly connected complex network that regulates their relative activities [ 30 , 31 ], it is likely that systems biology analyses will reveal regulatory interactions and feedback loops which are involved in altering GTPase activity and migratory phenotype. Boolean logic is an attractive modelling tool in the context of a large and essentially poorly characterised setting, since the detailed kinetic parameters (activation/inhibition rates, initial molecular concentrations) crucial to the generation of continuous models based on ordinary differential equations are not required [ 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion

et al. 2016

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Cell migration in 3D microenvironments is fundamental to development, homeostasis and the pathobiology of diseases such as cancer. Rab-coupling protein (RCP) dependent co-trafficking of α5β1 and EGFR1 promotes cancer cell invasion into fibronectin (FN) containing extracellular matrix (ECM), by potentiating EGFR1 signalling at the front of invasive cells. This promotes a switch in RhoGTPase signalling to inhibit Rac1 and activate a RhoA-ROCK-Formin homology domain-containing 3 (FHOD3) pathway and generate filopodial actin-spike protrusions which drive invasion. To further understand the signalling network that drives RCP-driven invasive migration, we generated a Boolean logical model based on existing network pathways/models, where each node can be interrogated by computational simulation. The model predicted an unanticipated feedback loop, whereby Raf/MEK/ERK signalling maintains suppression of Rac1 by inhibiting the Rac-activating Sos1-Eps8-Abi1 complex, allowing RhoA activity to predominate in invasive protrusions. MEK inhibition was sufficient to promote lamellipodia formation and oppose filopodial actin-spike formation, and led to activation of Rac and inactivation of RhoA at the leading edge of cells moving in 3D matrix. Furthermore, MEK inhibition abrogated RCP/α5β1/EGFR1-driven invasive migration. However, upon knockdown of Eps8 (to suppress the Sos1-Abi1-Eps8 complex), MEK inhibition had no effect on RhoGTPase activity and did not oppose invasive migration, suggesting that MEK-ERK signalling suppresses the Rac-activating Sos1-Abi1-Eps8 complex to maintain RhoA activity and promote filopodial actin-spike formation and invasive migration. Our study highlights the predictive potential of mathematical modelling approaches, and demonstrates that a simple intervention (MEK-inhibition) could be of therapeutic benefit in preventing invasive migration and metastasis.

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Phosphorylation-mediated regulation of GEFs for RhoA

Cited by 28 publications

References 84 publications

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

Phosphoproteomics of cAMP signaling of Bordetella adenylate cyclase toxin in mouse dendritic cells

A MAPK-Driven Feedback Loop Suppresses Rac Activity to Promote RhoA-Driven Cancer Cell Invasion

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