Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1

Meiri, David; Marshall, Christopher B.; Mokady, Daphna; LaRose, Jose; Mullin, Michael; Gingras, Anne‐Claude; Ikura, Mitsuhiko; Rottapel, Robert

doi:10.1038/ncomms5857

Cited by 52 publications

(57 citation statements)

References 43 publications

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“…This indicates that mechanical-stretch induced GEF-H1 activation mainly depends on microtubule depolymerization in cardiomyocytes. As the residual GEF-H1 activation in Nox2-silencing NRCMs was completely abolished by okadaic acid, an inhibitor of PP2A phosphatase, which is reported to positively regulates GEH-H1 activity in a microtubule-independent manner26 (Fig. 5e).…”

Section: Resultsmentioning

confidence: 85%

“…GEF-H1 is predominantly localized in microtubules, and both microtubule-dependent and –independent activation mechanism are involved in ligand-stimulated GEF-H1 activation26. Our previous study suggested a functional coupling between TRPC3 and microtubule-associated Nox2, and that TRPC3/Nox2-mediated production of reactive oxygen species (ROS) is highly correlated with the severity of heart failure19.…”

Section: Resultsmentioning

confidence: 99%

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TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

Numaga‐Tomita

Kitajima

Kuroda

et al. 2016

Sci Rep

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Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

Numaga‐Tomita

Kitajima

Kuroda

et al. 2016

Sci Rep

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“…These G-protein-coupled receptors trigger the dissociation of the Rho activator guanine exchange factor H1 (GEFH1) from microtubules, allowing it to activate Rho. 48 Subsequently, Rho, via Rho kinase, increases myosin activity and destabilizes EC-cell adhesions ( Figure 2). 47,[49][50][51][52][53] Thrombin-induced EC contractility, ECderived traction forces, and monolayer permeability are enhanced on stiffening substrates.…”

Section: Stiffness-induced Regulation Of Endothelial Permeabilitymentioning

confidence: 99%

Between Rho(k) and a Hard Place

Huveneers

Daemen

Hordijk

2015

Circulation Research

157

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Vascular stiffness is a mechanical property of the vessel wall that affects blood pressure, permeability, and inflammation. As a result, vascular stiffness is a key driver of (chronic) human disorders, including pulmonary arterial hypertension, kidney disease, and atherosclerosis. Responses of the endothelium to stiffening involve integration of mechanical cues from various sources, including the extracellular matrix, smooth muscle cells, and the forces that derive from shear stress of blood. This response in turn affects endothelial cell contractility, which is an important property that regulates endothelial stiffness, permeability, and leukocyte-vessel wall interactions. Moreover, endothelial stiffening reduces nitric oxide production, which promotes smooth muscle cell contraction and vasoconstriction. In fact, vessel wall stiffening, and microcirculatory endothelial dysfunction, precedes hypertension and thus underlies the development of vascular disease. Here, we review the cross talk among vessel wall stiffening, endothelial contractility, and vascular disease, which is controlled by Rho-driven actomyosin contractility and cellular mechanotransduction. In addition to discussing the various inputs and relevant molecular events in the endothelium, we address which actomyosin-regulated changes at cell adhesion complexes are genetically associated with human cardiovascular disease. Finally, we discuss recent findings that broaden therapeutic options for targeting this important mechanical signaling pathway in vascular pathogenesis. vascular stiffening) and the various external cues that regulate this. In addition, we will discuss the relationship between endothelial contractility and leukocyte extravasation and finally address (future) possibilities to therapeutically target ECs to reduce chronic, stiffness-related, vascular inflammation. Systemic Regulation of Vascular StiffnessArterial stiffness is strongly associated with high blood pressure, as well as with aging, and serves as an independent predictor of human cardiovascular disease. An elevation in arterial stiffness increases systolic blood pressure, thereby promoting cardiac hypertrophy, and decreases the diastolic blood pressure which is a trigger for developing myocardial ischemia. 7 Aortic stiffness also affects the microcirculation and vice versa, microcirculatory changes affect aortic stiffness. Stiffening of the aortic wall leads to increased pulse wave velocity (PWV) and premature reflected waves with elevated systolic and pulsatile central hemodynamic load resulting in microcirculatory damages in peripheral tissues. Conversely, microvasculature remodeling elevates systemic vascular resistance and pulse wave reflection, which stiffens the aortic wall, indicating that the endothelium has both a responsive and a causal role in vascular stiffening. 7 Increased PWV accurately estimates arterial wall stiffness and has recently been included in official hypertension guidelines. PWV values increase with age, and increases in aortic PWV is a g...

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“…DYNLT1 can function in dynein-independent fashion as a cell fate regulator by its interaction with G-protein ␤ ␥ subunit regulating initial neurite sprouting (18), axonal specification, and elongation of hippocampal neurons in culture (11,19). GEF-H1 is bound to microtubules by DYNLT1 and its release without microtubule depolymerization is mediated through the interaction of DYNLT1 with G proteins (20). DYNLT1 is a novel marker for neural progenitors in adult brain (21).…”

mentioning

confidence: 99%

Aberrant Expression of Dynein light chain 1 (DYNLT1) is Associated with Human Male Factor Infertility*

Sivankutty

Sekhar

Sengottaiyan

et al. 2015

Molecular & Cellular Proteomics

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DYNLT1 is a member of a gene family identified within the t-complex of the mouse, which has been linked with male germ cell development and function in the mouse and the fly. Though defects in the expression of this gene are associated with male sterility in both these models, there has been no study examining its association with spermatogenic defects in human males. In this study, we evaluated the levels of DYNLT1 and its expression product in the germ cells of fertile human males and males suffering from spermatogenic defects. We screened fertile (n = 14), asthenozoospermic (n = 15), oligozoospermic (n = 20) and teratozoospermic (n = 23) males using PCR and Western blot analysis. Semiquantitative PCR indicated either undetectable or significantly lower levels of expression of DYNLT1 in the germ cells from several patients from across the three infertility syndrome groups, when compared with that of fertile controls. DYNLT1 was localized on head, mid-piece, and tail segments of spermatozoa from fertile males. Spermatozoa from infertile males presented either a total absence of DYNLT1 or its absence in the tail region. Majority of the infertile individuals showed negligible levels of localization of DYNLT1 on the spermatozoa. Overexpression of DYNLT1 in GC1-spg cell line resulted in the up-regulation of several cytoskeletal proteins and molecular chaperones involved in cell cycle regulation. Defective expression of DYNLT1 was associated with male factor infertility syndromes in our study population. Proteome level changes in GC1-spg cells overexpressing DYNLT1 were suggestive of its possible function in germ cell development. We have discussed the implications of these observations in the light of the known functions of DYNLT1, which included protein trafficking, membrane vesiculation, cell cycle regulation, and stem cell differentiation. Molecular & Cellular Proteomics 14: 10.1074/mcp.M115.050005, 3185-3195, 2015.

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Mechanistic insight into GPCR-mediated activation of the microtubule-associated RhoA exchange factor GEF-H1

Cited by 52 publications

References 43 publications

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

Between Rho(k) and a Hard Place

Aberrant Expression of Dynein light chain 1 (DYNLT1) is Associated with Human Male Factor Infertility*

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