Open questions: what about the ‘other’ Rho GTPases?

Ridley, Anne J.

doi:10.1186/s12915-016-0289-7

Cited by 4 publications

(5 citation statements)

References 10 publications

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“…While RhoA has been shown to contribute to the mechano-transduction and phenotypic regulation in valvular cells, mainly of aortic valve origin, it is to our knowledge the first report of the implication of RhoC and not RhoA, in this process probably because of the very specific molecular tools that we used. Although some studies suggest the redundant roles between RhoA and RhoC, their different modulation by the numerous regulatory factors, GEFs, GAPs and GDI, strongly suggests that they play also context-and localization-dependent distinct roles [45,46]. ROCK is a downstream effector of RhoA and RhoC.…”

Section: Discussionmentioning

confidence: 99%

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Blomme

Deroanne

Hulin

et al. 2019

Journal of Molecular and Cellular Cardiology

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The mitral valve is a complex multilayered structure populated by fibroblast-like cells, valvular interstitial cells (VIC) which are embedded in an extracellular matrix (ECM) scaffold and are submitted to the mechanical deformations affecting valve at each heartbeat, for an average of 40 million times per year. Myxomatous mitral valve (MMV) is the most frequent heart valve disease characterized by disruption of several valvular structures due to alterations of their ECM preventing the complete closure of the valve resulting in symptoms of prolapse and regurgitation. VIC and their ECM exhibit reciprocal dynamic processes between the mechanical signals issued from the ECM and the modulation of VIC phenotype responsible for ECM homeostasis of the valve. Abnormal perception and responsiveness of VIC to mechanical stress may induce an inappropriate adaptative remodeling of the valve progressively leading to MMV. To investigate the response of human VIC to mechanical strain and identify the molecular mechanisms of mechano-transduction in these cells, a cyclic equibiaxial elongation of 14% at the cardiac frequency of 1.16 Hz was applied to VIC by using a Flexercell-4000 T™ apparatus for increasing time (from 1 h to 8 h). We showed that cyclic stretch induces an early (1 h) and transient over-expression of TGFβ2 and αSMA. CTGF, a profibrotic growth factor promoting the synthesis of ECM components, was strongly induced after 1 and 2 h of stretching and still upregulated at 8 h. The mechanical stress-induced CTGF up-regulation was dependent on RhoC, but not RhoA, as demonstrated by siRNA-mediated silencing approaches, and further supported by evidencing RhoC activation upon cell stretching and suppression of cell response by pharmacological inhibition of the effector ROCK1/2. It was also dependent on the MEK/Erk1/2 pathway which was activated by mechanical stress independently of RhoC and ROCK. Finally, mechanical stretching induced the nuclear translocation of myocardin related transcription factor-A (MRTF-A) which forms a transcriptional complex with SRF to promote the expression of target genes, notably CTGF. Treatment of stretched cultures with inhibitors of the identified pathways (ROCK1/2, MEK/ Erk1/2, MRTF-A translocation) blocked CTGF overexpression and abrogated the increased MRTF-A nuclear translocation. CTGF is up-regulated in many pathological processes involving mechanically challenged organs, promotes ECM accumulation and is considered as a hallmark of fibrotic diseases. Pharmacological targeting of MRTF-A by newly developed inhibitors may represent a relevant therapy for MMV.

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Section: Discussionmentioning

confidence: 99%

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Blomme

Deroanne

Hulin

et al. 2019

Journal of Molecular and Cellular Cardiology

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“…Most of the earlier studies on Rho described above have been carried out on RhoA, and it is not certain whether other Rho members exert the same actions in the cell. Although some studies suggest the redundant roles between these RhoA, RhoB, and RhoC isoforms , their different cellular localization and different regulatory modes of expression strongly suggest that they play also context‐ and localization‐dependent distinct roles in the cell and possibly in the body . For example, although these three Rho members similarly interact with Rho effectors thus far identified, RhoA, RhoB, and RhoC act on different effectors, namely ROCKi/2, integrins and formin FMNL3, respectively, and exert different functions in cancer cell migration and morphogenesis .…”

Section: Future Prospectsmentioning

confidence: 99%

“…Furthermore, while RhoA‐null mice are embryonic lethal , RhoB‐null and RhoC‐null mice are viable . There are also issues on atypical Rho GTPases such as Rnd proteins, RhoBTB proteins, RhoH, RhoU and RhoV . More remains to be clarified on their regulatory and effector mechanisms, and again their body function.…”

Section: Future Prospectsmentioning

confidence: 99%

Rho signaling research: history, current status and future directions

2018

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One of the main research areas in biology from the mid‐1980s through the 1990s was the elucidation of signaling pathways governing cell responses. These studies brought, among other molecules, the small GTPase Rho to the epicenter. Rho signaling research has since expanded to all areas of biology and medicine. Here, we describe how Rho emerged as a key molecule governing cell morphogenesis and movement, how it was linked to actin reorganization, and how the study of Rho signaling has expanded from cultured cells to whole biological systems. We then give an overview of the current research status of Rho signaling in development, brain, cardiovascular system, immunity and cancer, and discuss the future directions of Rho signaling research, with emphasis on one Rho effector, ROCK*. *The Rho GTPase family. Rho family GTPases have now expanded to contain 20 members. Amino acid sequences of 20 Rho GTPases found in human were aligned and the phylogenetic tree was generated by ClustalW2 software (EMBL‐EBI) based on NJ algorithm. The subfamilies of the Rho GTPases are highlighted by the circle and labeled on the right side. Rho cited in this review refers to the original members of Rho subfamily, RhoA, RhoB and RhoC, that are C3 substrates, and, unless specified, not to other members of the Rho subfamily such as Rac, Cdc42, and Rnd.

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“…Characterising the regulation and mechanism of GEF activity itself is subject to similar experimental constraints. Moreover, obscurin has only been tested against four GTPases although the Rho-family features more than 20 members, many of which could be potential substrates of the obscurin RhoGEF domains [ 11 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro

et al. 2023

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Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can activate the small GTPases RhoA and RhoQ in cells, in vitro characterization of these interactions using biophysical techniques has been hampered by the intrinsic instability of obscurin GEF domains. To study substrate specificity, mechanism and regulation of obscurin GEF function by individual domains, we successfully optimized recombinant production of obscurin GEF domains and found that MST-family kinases phosphorylate the obscurin DH domain at Thr5798. Despite extensive testing of multiple GEF domain fragments, we did not detect any nucleotide exchange activity in vitro against 9 representative small GTPases. Bioinformatic analyses show that obscurin differs from other Trio-subfamily GEFs in several important aspects. While further research is necessary to evaluate obscurin GEF activity in vivo, our results indicate that obscurin has atypical GEF domains that, if catalytically active at all, are subject to complex regulation.

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Open questions: what about the ‘other’ Rho GTPases?

Abstract: Rho GTPases have many and diverse roles in cell physiology, and some family members are very well studied, including RhoA, Rac1 and Cdc42. But many are relatively neglected, and fundamental questions about their mechanisms and functions remain open.

Cited by 4 publications

References 10 publications

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways

Rho signaling research: history, current status and future directions

Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro

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