Angiogenesis: The Importance of RHOJ-Mediated Trafficking of Active Integrins

Valdembri, Donatella; Serini, Guido

doi:10.1016/j.cub.2020.04.004

Cited by 7 publications

(3 citation statements)

References 20 publications

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“…Rho GTPase signaling networks are critical to the vascular structure and tumor angiogenesis [37]. The small Rho GTPase RhoJ is abundantly expressed in endothelial cells during tumor progression, and its role in angiogenesis has been extensively reported [38][39][40]. Recent studies have revealed that RhoJ blockade destroys tumor blood vessels by activating the RhoA-ROCK signaling pathway in various tumor models.…”

Section: Discussionmentioning

confidence: 99%

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

Wang¹,

Zhang²,

Zheng³

et al. 2022

Int. J. Biol. Sci.

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Glioblastoma (GBM) is a highly vascularized malignant tumor that depends on new blood vessel formation. Small molecules targeting the angiogenic process may be an effective anti-GBM therapeutic strategy. We previously demonstrated that RhoJ promoted the progression and invasion of GBM. RhoJ has also been shown to be expressed in endothelial cells and plays an important role in regulating endothelial cell migration and tumor angiogenesis. Therefore, we aimed to evaluate the role and mechanism of actions of RhoJ in GBM angiogenesis. We analyzed the expression of RhoJ in different grade gliomas and investigated its role in GBM angiogenesis in vivo and in vitro. Furtherly, RNA sequencing (RNA-seq), Western blotting and immunofluorescence were performed to identify the molecular mechanism of RhoJ in regulating endothelial cell behavior and GBM angiogenesis. Here, we found that silencing RhoJ resulted in inhibition of HUVEC cell migration and blood vessel formation. Overexpression of RhoJ promoted the expression of CD31, EpCAM and moesin, suggesting RhoJ facilitated angiogenesis and the malignant progression of GBM. RNA-seq data showed that VEGF/TNF signaling pathway positively regulated RhoJ. The expression levels of RhoJ was upregulated with the stimulation of VEGF, and reduced by the treatment of JNK inhibitor SP600125. It was also found that the activity of PAK-BRAF-ERK was down-regulated upon RhoJ and JNK knockdown. In conclusion, these results suggested that RhoJ plays an essential role in regulating GBM angiogenesis through the JNK/VEGFR2-PAK-ERK signaling pathway and there might exist a VEGF-JNK/ERK-VEGF circuitry. Thus, RhoJ may be a candidate therapeutic target for anti-angiogenesis treatment in GBM.

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Section: Discussionmentioning

confidence: 99%

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

Wang¹,

Zhang²,

Zheng³

et al. 2022

Int. J. Biol. Sci.

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“…Relevant studies have shown RHO GTPases signaling contributes to the malignant progression of cancer and some RHO GTPases emerge as a potential therapeutic target [20][21][22][23] , and a new study has uncovered that RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy [24] . In addition, RHOJ interruption has been reported as an effective therapeutic option for targeting the tumor vascular system [25][26][27] . Our recent studies also showed that RHOJ is significantly overexpressed in glioblastoma and facilitates angiogenesis and tumor invasion [28,29] .…”

Section: Introductionmentioning

confidence: 99%

RHOJ Induces Epithelial-to-Mesenchymal Transition by IL-6/STAT3 to Promote Invasion and Metastasis in Gastric Cancer

Ma,

Sun,

Zhang

et al. 2023

Int. J. Biol. Sci.

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Background: Recently, the molecular classification of gastric cancer (GC) promotes the advances of GC patients' precision therapy and prognosis prediction. According to the Asian Cancer Research Group (ACRG), GC is classified as microsatellite instable (MSI) subtype GC, microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT) subtype GC, MSS/TP53- subtype GC, and MSS/TP53+ subtype GC. Due to the easy metastasis of EMT-subtype GC, it has the worst prognosis, the highest recurrence rate, and the tendency to occur at a younger age. Therefore, it is curious and crucial for us to understand the molecular basis of EMT-subtype GC. Methods: The expression of RHOJ was detected by quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) in GC cells and tissues. Western blotting and immunofluorescence (IF) were conducted to examine the effects of RHOJ on the EMT markers' expression of GC cells. The GC cells' migration and invasion were investigated by transwell assay. The tumor growth and metastasis were demonstrated correspondingly in different xenograft models. Results: Firstly, it was noticed that RHOJ was significantly upregulated in EMT-subtype GC and RHOJ has close relationships with the EMT process of GC, based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Next, transwell assay and tail vein metastasis models were conducted to verify that RHOJ mediates the EMT to regulate the invasion and metastasis of GC in vitro and in vivo . In addition, weakened tumor angiogenesis was observed after RHOJ knockdown by the angiogenesis assay of HUVEC. RNA-seq and further study unveiled that RHOJ aggravates the malignant progression of GC by inducing EMT through IL-6/STAT3 to promote invasion and metastasis. Finally, blocking the IL-6/STAT3 signaling overcame RHOJ-mediated GC cells' growth and migration. Conclusions: These results indicate that the upregulation of RHOJ contributes to EMT-subtype GC invasion and metastasis via IL-6/STAT3 signaling, and RHOJ is expected to become a promising biomarker and therapeutic target for EMT-subtype GC patients.

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“…FMNL2 regulates β1 integrin internalization [ 29 ] but is reported to be absent in endothelial cells [ 30 ]. Therefore, the closely related protein FMNL3, already known to function downstream of RhoJ during lumenisation [ 19 ] and downstream of Cdc42 at the Golgi during anterograde trafficking [ 31 ] is a likely shared effector that could regulate RhoJ-dependent regulation of active α5β1 trafficking [ 32 ].…”

mentioning

confidence: 99%

A functional antagonism between RhoJ and Cdc42 regulates fibronectin remodelling during angiogenesis

Sundararaman

Mellor

2020

Small GTPases

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Angiogenesis is the formation of new blood vessels from pre-existing ones. Angiogenesis requires endothelial cells to change shape and polarity, as well as acquire the ability to directionally migrateprocesses that are classically regulated by the Rho family of GTPases. RhoJ (previously TCL) is an endothelium enriched Rho GTPase with a 78% amino acid similarity to the ubiquitously expressed Cdc42. In our recent publication, we demonstrate that α5β1 integrin co-traffics with RhoJ. RhoJ specifically represses the internalization of the active α5β1 conformer, leading to a reduced ability of endothelial cells to form fibronectin fibrils. Surprisingly, this function of RhoJ is in opposition to the role of Cdc42, a known driver of fibrillogenesis. Intriguingly, we discovered that the competition for limiting amounts of the shared effector, PAK3, could explain the ability of these two Rho GTPases to regulate fibrillogenesis in opposing directions. Consequently, RhoJ null mice show excessive fibronectin deposition around retinal vessels, possibly due to the unopposed action of Cdc42. Our work suggests that the functional antagonism between RhoJ and Cdc42 could restrict fibronectin remodelling to sites of active angiogenesis to form a provisional matrix for vessel growth. One correlate of our findings is that RhoJ dependent repression of fibronectin remodelling could be atheroprotective in quiescent vessels.

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Angiogenesis: The Importance of RHOJ-Mediated Trafficking of Active Integrins

Cited by 7 publications

References 20 publications

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

RhoJ facilitates angiogenesis in glioblastoma via JNK/VEGFR2 mediated activation of PAK and ERK signaling pathways

RHOJ Induces Epithelial-to-Mesenchymal Transition by IL-6/STAT3 to Promote Invasion and Metastasis in Gastric Cancer

A functional antagonism between RhoJ and Cdc42 regulates fibronectin remodelling during angiogenesis

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