Guanine nucleotide exchange factors for Rho GTPases (RhoGEFs) as oncogenic effectors and strategic therapeutic targets in metastatic cancer

Cervantes‐Villagrana, Rodolfo Daniel; García‐Jiménez, Irving; Vázquez‐Prado, José

doi:10.1016/j.cellsig.2023.110749

Cited by 9 publications

(9 citation statements)

References 274 publications

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“…These results contribute to explain the contrasting functional effects of different Rho GTPases, particularly Cdc42 and RhoJ, which, given their high homology, could be expected to be functionally redundant [38,39], and open new avenues to explore the regulation by oncogenic Gαq of RhoJ effectors, which has, so far, been linked to vascular endothelial growth factor receptor and Semaphorin E/Plexin D signaling [40]. In uveal melanoma cells, the oncogenic effect of Gαq-Q209L is, at least in part, mediated by Trio [38,39], and our results add PDZ-RhoGEF to the repertoire of oncogenic effectors, warranting further investigations pointing to their potential as drug targets of metastatic cancers [37]. Although our current results are consistent with the potential oncogenic role of the Gαq-Q209L/PDZ-RhoGEF/RhoJ axis, we should keep in mind that this emerging possibility warrants future investigations in preclinical models of uveal melanoma.…”

Section: Discussionmentioning

confidence: 56%

“…Preclinical investigations have characterized PDZ-RhoGEF, a multidomain signaling effector, as a critical participant in the progression of various cancer types, including glioblastoma and ovarian cancer [31,36]. The gene coding for this RhoGEF has been found to be amplified in human breast invasive carcinoma and lung adenocarcinoma [37]. Based on the current studies, and previous findings, as a signaling platform that integrates heterotrimeric G protein signaling, leading to adjustments in the actin cytoskeleton, PDZ-RhoGEF might serve as an effector to fine-tune dynamic adjustments of migrating cancer cells, depending on the signaling input and the small Rho GTPase being activated: RhoA, Cdc42, or RhoJ.…”

Section: Discussionmentioning

confidence: 99%

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Oncogenic Gαq activates RhoJ through PDZ-RhoGEF

Cervantes-Villagrana,

Color-Aparicio,

Castillo-Kauil

et al. 2023

IJMS

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Oncogenic Gαq causes uveal melanoma via non-canonical signaling pathways. This constitutively active mutant GTPase is also found in cutaneous melanoma, lung adenocarcinoma, and seminoma, as well as in benign vascular tumors, such as congenital hemangiomas. We recently described that PDZ-RhoGEF (also known as ARHGEF11), a canonical Gα12/13 effector, is enabled by Gαs Q227L to activate CdcIn addition, and we demonstrated that constitutively active Gαq interacts with the PDZ-RhoGEF DH-PH catalytic module, but does not affect its binding to RhoA or Cdc. This suggests that it guides this RhoGEF to gain affinity for other GTPases. Since RhoJ, a small GTPase of the Cdc42 subfamily, has been involved in tumor-induced angiogenesis and the metastatic dissemination of cancer cells, we hypothesized that it might be a target of oncogenic Gαq signaling via PDZ-RhoGEF. Consistent with this possibility, we found that Gαq Q209L drives full-length PDZ-RhoGEF and a DH-PH construct to interact with nucleotide-free RhoJ-G33A, a mutant with affinity for active RhoJ-GEFs. Gαq Q209L binding to PDZ-RhoGEF was mapped to the PH domain, which, as an isolated construct, attenuated the interaction of this mutant GTPase with PDZ-RhoGEF’s catalytic module (DH-PH domains). Expression of these catalytic domains caused contraction of endothelial cells and generated fine cell sprouts that were inhibited by co-expression of dominant negative RhoJ. Using relational data mining of uveal melanoma patient TCGA datasets, we got an insight into the signaling landscape that accompanies the Gαq/PDZ-RhoGEF/RhoJ axis. We identified three transcriptional signatures statistically linked with shorter patient survival, including GPCRs and signaling effectors that are recognized as vulnerabilities in cancer cell synthetic lethality datasets. In conclusion, we demonstrated that an oncogenic Gαq mutant enables the PDZ-RhoGEF DH-PH module to recognize RhoJ, suggesting an allosteric mechanism by which this constitutively active GTPase stimulates RhoJ via PDZ-RhoGEF. These findings highlight PDZ-RhoGEF and RhoJ as potential targets in tumors driven by mutant Gαq.

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Section: Discussionmentioning

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Oncogenic Gαq activates RhoJ through PDZ-RhoGEF

Cervantes-Villagrana,

Color-Aparicio,

Castillo-Kauil

et al. 2023

IJMS

Self Cite

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“…Indeed, more than 40% of breast tumors in The Cancer Genome Atlas (TCGA) cohort show deletions that included ARHGAP44 and ABR on 17p, ARHGAP20 and ARHGAP32 on 11q, STARD13/DLC2 on 13q, as well as PRR5/ARHGAP8 , SH3BP1 and BCR on 22q (Additional file 1 : Supplementary Figure S1A, S1B). Copy number gains and structural variants in RhoGEF genes were also evident, many of which have the potential to increase Rho signaling through increased GTP-loading [ 6 ]. For example, over 50% of TCGA breast tumors show copy number gains or amplifications involving OBSCN, ARHGEF2 and ARHGEF11 on 1q or PREX2 on 8q (Additional file 1 : Supplementary Figure S1C, S1D).…”

Section: Resultsmentioning

confidence: 99%

“…Upstream, p53 and Ets transcription factors, as well as microRNAs play an important role in controlling RhoC protein expression. RhoGDI, RhoGAP and RhoGEF proteins control GTP-loading [ 4 – 6 ]. Whereas Rock kinases, Rac and Cdc42, Formin-like proteins, as well as microfilaments and microtubules seem to play important roles downstream [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation

Raghuram,

Temel,

Kawamata

et al. 2024

Breast Cancer Res

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Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. RhoC overexpression also enhanced mammary tumor formation in an activated Pik3ca model for breast cancer (Pik3caH1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3caH1047R systems. Thus, our study reveals the importance of elevated wildtype Rho protein expression as a driver of breast tumor formation and highlights the significance of Copy Number Abberations that affect Rho signalling.

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“…Allostery is also involved in K-Ras4B–SOS1 activation . Recently, RhoGEFs have been identified as therapeutic targets for metastatic cancers. , Knowledge of the allosteric interactions taking place during the activation of RhoA by p115-RhoGEF, as well as the differences in the conformational dynamics between the active and inactive complexes, can shed further light on the RhoA activation process and mechanism and can help in drug design.…”

Section: Discussionmentioning

confidence: 99%

Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

Haspel,

Jang,

Nussinov

2024

J. Chem. Inf. Model.

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The Ras homologue family member A (RhoA) is a member of the Rho family, a subgroup of the Ras superfamily. RhoA interacts with the 115 kDa guanine nucleotide exchange factor (p115-RhoGEF), which assists in activation and binding with downstream effectors. Here, we use molecular dynamics (MD) simulations and essential dynamics analysis of the inactive RhoA− GDP and active RhoA−GTP, when bound to p115-RhoGEF to decipher the mechanism of RhoA activation at the structural level. We observe that inactive RhoA−GDP maintains its position near the catalytic site on the Dbl homology (DH) domain of p115-RhoGEF through the interaction of its Switch I region with the DH domain. We further show that the active RhoA−GTP is engaged in more interactions with the p115-RhoGEF membrane-bound Pleckstrin homology (PH) domain as compared to RhoA−GDP. We hypothesize that the role of the interactions between the active RhoA−GTP and the PH domain is to help release it from the DH domain upon activation. Our results support this premise, and our simulations uncover the beginning of this process and provide structural details. They also point to allosteric communication pathways that take part in RhoA activation to promote and strengthen the interaction between the active RhoA−GTP and the PH domain. Allosteric regulation also occurs among other members of the Rho superfamily. Collectively, we suggest that in the activation process, the role of the RhoA−GTP interaction with the PH domain is to release RhoA−GTP from the DH domain after activation, making it available to downstream effectors.

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Guanine nucleotide exchange factors for Rho GTPases (RhoGEFs) as oncogenic effectors and strategic therapeutic targets in metastatic cancer

Cited by 9 publications

References 274 publications

Oncogenic Gαq activates RhoJ through PDZ-RhoGEF

Oncogenic Gαq activates RhoJ through PDZ-RhoGEF

Elevated expression of wildtype RhoC promotes ErbB2- and Pik3ca-induced mammary tumor formation

Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics

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