The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium

Kempers, Lanette; Driessen, Amber J. M.; Rijssel, Jos van; Nolte, Martijn A.; Buul, Jaap D. van

doi:10.3390/ijms221810168

Cited by 9 publications

(4 citation statements)

References 101 publications

(140 reference statements)

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“…However, the absence of a similar phenotype in the Dock10 CKO mouse suggests that the role of Dock10 in maintaining normal cardiac function probably lies in cells other than cardiomyocytes. Indeed, while alterations in the Cdc42 and Rac1 signaling of cardiomyocytes affect the development of cardiac hypertrophy and heart failure, these Rho GTPases can have important roles in other cell types of crucial importance in the heart, including cardiofibroblasts [ 36 , 37 ] and endothelial cells [ 38 , 39 ]. In addition, the well-documented function of Dock10 in immune cells, including macrophages [ 16 , 17 , 19 ], may also be considered as a possible mechanism that leads to the observed phenotype in the global Dock10 KO mice [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Dock10 Regulates Cardiac Function under Neurohormonal Stress

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Etzion

Elyagon

et al. 2022

IJMS

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Dedicator of cytokinesis 10 (Dock10) is a guanine nucleotide exchange factor for Cdc42 and Rac1 that regulates the JNK (c-Jun N-terminal kinase) and p38 MAPK (mitogen-activated protein kinase) signaling cascades. In this study, we characterized the roles of Dock10 in the myocardium. In vitro: we ablated Dock10 in neonatal mouse floxed Dock10 cardiomyocytes (NMCMs) and cardiofibroblasts (NMCFs) by transduction with an adenovirus expressing Cre-recombinase. In vivo, we studied mice in which the Dock10 gene was constitutively and globally deleted (Dock10 KO) and mice with cardiac myocyte-specific Dock10 KO (Dock10 CKO) at baseline and in response to two weeks of Angiotensin II (Ang II) infusion. In vitro, Dock10 ablation differentially inhibited the α-adrenergic stimulation of p38 and JNK in NMCM and NMCF, respectively. In vivo, the stimulation of both signaling pathways was markedly attenuated in the heart. The Dock10 KO mice had normal body weight and cardiac size. However, echocardiography revealed mildly reduced systolic function, and IonOptix recordings demonstrated reduced contractility and elevated diastolic calcium levels in isolated cardiomyocytes. Remarkably, Dock10 KO, but not Dock10 CKO, exaggerated the pathological response to Ang II infusion. These data suggest that Dock10 regulates cardiac stress-related signaling. Although Dock10 can regulate MAPK signaling in both cardiomyocytes and cardiofibroblasts, the inhibition of pathological cardiac remodeling is not apparently due to the Dock10 signaling in the cardiomyocyte.

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Section: Discussionmentioning

confidence: 99%

Dock10 Regulates Cardiac Function under Neurohormonal Stress

Segal

Etzion

Elyagon

et al. 2022

IJMS

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“…Trio, which possess three enzymatic domains, has shown its importance in the endothelial cells’ morphology and barrier function. In their review, Kempers et al focus on the function of Trio signaling in the healthy endothelium and on Trio dysregulation in vascular-related inflammatory diseases [ 8 ]. The migration of ECs is an essential process for the blood vessel formation.…”

Section: Endothelial Cell Signaling In Endothelial Cell Function and ...mentioning

confidence: 99%

Advances in Endothelial Cell Biology: From Knowledge to Control

Charreau

2022

IJMS

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The aim of this Special Issue is to provide an overview of recent investigations in the field of endothelial cell (EC) biology that advance our understanding of the molecular mechanisms that trigger normal EC functions and dysfunctions in pathologies and to demonstrate how improved knowledge of EC biology may lead to the discovery of novel molecular diagnostic technologies and targeted therapeutics [...]

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“…These confusing results point to different signaling pathways for wildtype and mutant RAC1. Disassembly of invadopodia has been related to a TRIOGEF-RAC1-PAK1-cortactin pathway [ 44 ]. Increased number of lamellipodia in melanoma cells expressing mutant RAC1 compared to wildtype has also been described by Mohan et al [ 45 ].…”

Section: Rac1 Signaling In Tumor Cell Migration and Invasionmentioning

confidence: 99%

RAC1 Activation as a Potential Therapeutic Option in Metastatic Cutaneous Melanoma

2021

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Metastasis is a complex process by which cancer cells escape from the primary tumor to colonize distant organs. RAC1 is a member of the RHO family of small guanosine triphosphatases that plays an important role in cancer migration, invasion, angiogenesis and metastasis. RAC1 activation has been related to most cancers, such as cutaneous melanoma, breast, lung, and pancreatic cancer. RAC1P29S driver mutation appears in a significant number of cutaneous melanoma cases. Likewise, RAC1 is overexpressed or hyperactivated via signaling through oncogenic cell surface receptors. Thus, targeting RAC1 represents a promising strategy for cutaneous melanoma therapy, as well as for inhibition of other signaling activation that promotes resistance to targeted therapies. In this review, we focus on the role of RAC1 in metastatic cutaneous melanoma emphasizing the anti-metastatic potential of RAC1- targeting drugs.

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The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium

Cited by 9 publications

References 101 publications

Dock10 Regulates Cardiac Function under Neurohormonal Stress

Dock10 Regulates Cardiac Function under Neurohormonal Stress

Advances in Endothelial Cell Biology: From Knowledge to Control

RAC1 Activation as a Potential Therapeutic Option in Metastatic Cutaneous Melanoma

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