RHOA takes the RHOad less traveled to cancer

Schaefer, Antje; Der, Channing J.

doi:10.1016/j.trecan.2022.04.005

Cited by 19 publications

(10 citation statements)

References 82 publications

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“…Therefore, disease-causing mutations in TRPV4 likely weaken the interactions with RhoA 22 . Notably, we also found that several cancer-related mutation sites in RhoA, such as A3, R5, and E50 [36][37][38] , are located at the interface with the TRPV4 ARD (Figs. 4b,c), providing evidence for an interplay between TRPV4 and RhoA in cancer 5,21,39 , although these RhoA mutations may also impact effector binding more broadly.…”

Section: Neuropathy Mutations Disrupt Rhoa Binding To Trpv4mentioning

confidence: 65%

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Kwon

Zhang

McCray

et al. 2023

Preprint

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Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the apo, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that the interaction strength between TRPV4 and RhoA tunes TRPV4-mediated calcium homeostasis and actin remodeling, and that disruption of TRPV4-RhoA interactions leads to TRPV4-related neuromuscular disease, findings that will guide TRPV4 therapeutics development.

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Section: Neuropathy Mutations Disrupt Rhoa Binding To Trpv4mentioning

confidence: 65%

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Kwon

Zhang

McCray

et al. 2023

Preprint

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“…Targeting crosstalk between different small GTPases is another interesting avenue because accumulating evidence indicates that the transformation of RAS-driven tumor cells requires endogenous activities of Rho proteins or overexpression of Rho, Arf, and Ran. 526 KRAS G12C inhibitors have been reported to drive a pro-inflammatory tumor microenvironment and enhance the anti-tumor activity when combined with immune checkpoint blockade (ICB). 492 , 527 However, a recent study indicates that G12C inhibitor selectively synergizes with ICB in inflamed tumors but not in non-inflamed tumors, which addresses a strong immunogenicity dependency of synergizing KRAS G12C inhibitor with ICB and guides the selection of patients who might respond to this combination.…”

Section: Discussionmentioning

confidence: 99%

Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS

Yin

Huang

Petela

et al. 2023

Sig Transduct Target Ther

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Small GTPases including Ras, Rho, Rab, Arf, and Ran are omnipresent molecular switches in regulating key cellular functions. Their dysregulation is a therapeutic target for tumors, neurodegeneration, cardiomyopathies, and infection. However, small GTPases have been historically recognized as “undruggable”. Targeting KRAS, one of the most frequently mutated oncogenes, has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening, covalent ligands, macromolecule inhibitors, and PROTACs. Two KRASG12C covalent inhibitors have obtained accelerated approval for treating KRASG12C mutant lung cancer, and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets. New methods of targeting KRAS are quickly evolving, including transcription, immunogenic neoepitopes, and combinatory targeting with immunotherapy. Nevertheless, the vast majority of small GTPases and hotspot mutations remain elusive, and clinical resistance to G12C inhibitors poses new challenges. In this article, we summarize diversified biological functions, shared structural properties, and complex regulatory mechanisms of small GTPases and their relationships with human diseases. Furthermore, we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS. The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.

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“…Recently, targeted sequencing of nine patients identified an elevated frequency of MYC and RHOA mutations together with other genetic aberrations, including mutations in MEF2B and MYD88 [ 110 ]. Although the sample size was small, they found that RHOA mutations were predictive of a favourable outcome [ 110 ], potentially due to tumour suppressor functions for RHOA; although, this remains to be determined [ 111 ]. Kataoka et al (2019) described a significant enrichment of mutations in TET2 and DNMT3A in EBV+ DLBCL [ 112 ].…”

Section: Ebv+ Diffuse Large B-cell Lymphomamentioning

confidence: 99%

Epstein–Barr Virus and the Pathogenesis of Diffuse Large B-Cell Lymphoma

Ross

Leahy

Neylon

et al. 2023

Life

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Epstein–Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.

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RHOA takes the RHOad less traveled to cancer

Cited by 19 publications

References 82 publications

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Structural insights into TRPV4-Rho GTPase signaling complex function and disease

Targeting small GTPases: emerging grasps on previously untamable targets, pioneered by KRAS

Epstein–Barr Virus and the Pathogenesis of Diffuse Large B-Cell Lymphoma

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