Last update 01 Nov 2024

RhoA Y42C

Last update 01 Nov 2024

Basic Info

Synonyms-

Introduction-

Drugs associated with RhoA Y42C

RhoA Y42C(Revere)

Target

RhoA Y42C

Mechanism

RhoA Y42C inhibitors

Active Org.

Revere Pharmaceuticals, Inc.Startup

Originator Org.

Revere Pharmaceuticals, Inc.Startup

Active Indication

Stomach Cancer

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

BGS-1933

Target

RhoA Y42C

Mechanism

RhoA Y42C inhibitors

Active Org.

Bridgene Biosciences, Inc.

Originator Org.

Bridgene Biosciences, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with RhoA Y42C

100 Translational Medicine associated with RhoA Y42C

0 Patents (Medical) associated with RhoA Y42C

Literatures (Medical) associated with RhoA Y42C

01 Mar 2020·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

P-Tyr42 RhoA GTPase amplifies superoxide formation through p47phox, phosphorylated by ROCK

Q3 · BIOLOGY

Article

Author: Park, Jae-Bong ; Kim, Jae-Gyu ; Hamza, Amir ; Cap, Kim Cuong

Optimal levels of reactive oxygen species (ROS) play a critical role in cellular physiological function. For production of intracellular superoxide, NADPH oxidase is one of the sources. Rac1/2 and RhoA GTPases are involved in regulation of NADPH oxidase activity and Tyr42 phosphorylation of RhoA (p-Tyr42 RhoA) seems significant in this regard as it was recently shown that hydrogen peroxide was able to increase p-Tyr42 RhoA levels. Phorbol myristate acetate (PMA), a tumor promoter, also induces production of superoxides; PMA activates Src, a tyrosine kinase, and increases p-Tyr42 RhoA levels. In exploring the mechanism of PMA effects, we reduced RhoA levels in test cells with si-RhoA and then restoration of various versions of RhoA for effect in response of the cells to PMA and producing superoxides. Restoration of RhoA Y42F (a dephospho-mimic form) still had reduced superoxide formation in response to PMA, compared with WT and Y42E RhoA. This was similarly seen with assays for cell migration and proliferation with cells responding to PMA. Y27632, a ROCK (Rho associated coiled coil kinase) inhibitor, also inhibited superoxide production, and also reduced p-Y416 Src and p-p47phox levels. A ROCK active fragment was also able to phosphorylate p47phox at Ser345 residue (p-Ser345 p47phox), a component of NADPH oxidase. Overall, we demonstrate that p-Tyr42 RhoA levels increase following PMA treatment and this is through production of superoxide and activation of Src. These in turn amplify superoxide production through ROCK phophorylation of p47phox and maintain a positive feedback loop for superoxide generation, and contribute to tumor progression.

01 Nov 2017·Free Radical Biology and MedicineQ2 · MEDICINE

Tyr42 phosphorylation of RhoA GTPase promotes tumorigenesis through nuclear factor (NF)-κB

Q2 · MEDICINE

Article

Author: Choi, Eun-Kyoung ; Kim, Yong-Sun ; Park, Hwee-Seon ; Park, Jae-Bong ; Kim, Jae-Gyu ; Choi, Kyoung-Chan ; Hong, Chang-Won

Dysregulation of reactive oxygen species (ROS) levels is implicated in the pathogenesis of several diseases, including cancer. However, the molecular mechanisms for ROS in tumorigenesis have not been well established. In this study, hydrogen peroxide activated nuclear factor-κB (NF-κB) and RhoA GTPase. In particular, we found that hydrogen peroxide lead to phosphorylation of RhoA at Tyr42 via tyrosine kinase Src. Phospho-Tyr42 (p-Tyr42) residue of RhoA is a binding site for Vav2, a guanine nucleotide exchange factor (GEF), which then activates p-Tyr42 form of RhoA. P-Tyr42 RhoA then binds to IκB kinase γ (IKKγ), leading to IKKβ activation. Furthermore, RhoA WT and phospho-mimic RhoA, RhoA Y42E, both promoted tumorigenesis, whereas the dephospho-mimic RhoA, RhoA Y42F suppressed it. In addition, hydrogen peroxide induced NF-κB activation and cell proliferation, along with expression of c-Myc and cyclin D1 in the presence of RhoA WT and RhoA Y42E, but not RhoA Y42F. Indeed, levels of p-Tyr42 Rho, p-Src, and p-65 are significantly increased in human breast cancer tissues and show correlations between each of the two components. Conclusively, the posttranslational modification of as RhoA p-Tyr42 may be essential for promoting tumorigenesis in response to generation of ROS.

Oncology ReportsQ3 · MEDICINE

In�vivo effects of mutant RHOA on tumor formation in an orthotopic inoculation model

Q3 · MEDICINE

Article

Author: Nakano, Kiyotaka ; Ishimaru, Chisako ; Komura, Daisuke ; Suzuki, Masami ; Nishizawa, Takashi ; Fujii, Etsuko ; Aburatani, Hiroyuki ; Kuroiwa, Yoshie ; Ishikawa, Shumpei ; Monnai, Makoto

Ras homolog family member A (RHOA) mutations are driver genes in diffuse‑type gastric cancers (DGCs), and we previously revealed that RHOA mutations contribute to cancer cell survival and cell migration through their dominant negative effect on Rho‑associated kinase (ROCK) signaling in vitro. However, how RHOA mutations contribute to DGC development in vivo is poorly understood. In the present study, the contribution of RHOA mutations to tumor morphology was investigated using an orthotopic xenograft model using the gastric cancer cell line MKN74, in which wild‑type (WT) or mutated (Y42C and Y42S) RHOA had been introduced. When we conducted RNA sequencing to distinguish between the genes expressed in human tumor tissues from those in mouse stroma, the expression profiles of the tumors were clearly divided into a Y42C/Y42S group and a mock/WT group. Through gene set enrichment analysis, it was revealed that inflammation‑ and hypoxia‑related pathways were enriched in the mock/WT tumors; however, cell metabolism‑ and cell cycle‑related pathways such as Myc, E2F, oxidative phosphorylation and G2M checkpoint were enriched in the Y42C/Y42S tumors. In addition, the gene set related to ROCK signaling inhibition was enriched in the RHOA‑mutated group, which indicated that a series of events are related to ROCK inhibition induced by RHOA mutations. Histopathological analysis revealed that small tumor nests were more frequent in RHOA mutants than in the mock or WT group. In addition, increased blood vessel formation and infiltration of macrophages within the tumor mass were observed in the RHOA mutants. Furthermore, unlike mock/WT, the RHOA‑mutated tumor cells had little antitumor host reaction in the invasive front, which is similar to the pattern of mucosal invasion in clinical RHOA‑mutated DGC. These transcriptome and pathological analyses revealed that mutated RHOA functionally contributes to the acquisition of DGC features, which will accelerate our understanding of the contribution of RHOA mutations in DGC biology and the development of further therapeutic strategies.

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RhoA Y42C

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