Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der
{"title":"RHOA L57V drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling","authors":"Antje Schaefer, Richard G. Hodge, Haisheng Zhang, G. Aaron Hobbs, Julien Dilly, Minh V. Huynh, Craig M. Goodwin, Feifei Zhang, J. Nathaniel Diehl, Mariaelena Pierobon, Elisa Baldelli, Sehrish Javaid, Karson Guthrie, Naim U. Rashid, Emanuel F. Petricoin, Adrienne D. Cox, William C. Hahn, Andrew J. Aguirre, Adam J. Bass, Channing J. Der","doi":"10.1126/scisignal.adg5289","DOIUrl":null,"url":null,"abstract":"Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr <jats:sup>42</jats:sup> -to-Cys (Y42C) and Leu <jats:sup>57</jats:sup> -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA <jats:sup>Y42C</jats:sup> exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA <jats:sup>L57V</jats:sup> promotes DGC growth. In mouse gastric organoids with deletion of <jats:italic>Cdh1</jats:italic> , which encodes the cell adhesion protein E-cadherin, the expression of RHOA <jats:sup>L57V</jats:sup> , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA <jats:sup>L57V</jats:sup> also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA <jats:sup>L57V</jats:sup> retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr <jats:sup>42</jats:sup> and Leu <jats:sup>57</jats:sup> in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA <jats:sup>L57V</jats:sup> additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA <jats:sup>Y42C</jats:sup> . Our results reveal that RHOA <jats:sup>L57V</jats:sup> and RHOA <jats:sup>Y42C</jats:sup> drive the development of DGC through distinct biochemical and signaling mechanisms.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Signaling","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1126/scisignal.adg5289","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Cancer-associated mutations in the guanosine triphosphatase (GTPase) RHOA are found at different locations from the mutational hotspots in the structurally and biochemically related RAS. Tyr 42 -to-Cys (Y42C) and Leu 57 -to-Val (L57V) substitutions are the two most prevalent RHOA mutations in diffuse gastric cancer (DGC). RHOA Y42C exhibits a gain-of-function phenotype and is an oncogenic driver in DGC. Here, we determined how RHOA L57V promotes DGC growth. In mouse gastric organoids with deletion of Cdh1 , which encodes the cell adhesion protein E-cadherin, the expression of RHOA L57V , but not of wild-type RHOA, induced an abnormal morphology similar to that of patient-derived DGC organoids. RHOA L57V also exhibited a gain-of-function phenotype and promoted F-actin stress fiber formation and cell migration. RHOA L57V retained interaction with effectors but exhibited impaired RHOA-intrinsic and GAP-catalyzed GTP hydrolysis, which favored formation of the active GTP-bound state. Introduction of missense mutations at KRAS residues analogous to Tyr 42 and Leu 57 in RHOA did not activate KRAS oncogenic potential, indicating distinct functional effects in otherwise highly related GTPases. Both RHOA mutants stimulated the transcriptional co-activator YAP1 through actin dynamics to promote DGC progression; however, RHOA L57V additionally did so by activating the kinases IGF1R and PAK1, distinct from the FAK-mediated mechanism induced by RHOA Y42C . Our results reveal that RHOA L57V and RHOA Y42C drive the development of DGC through distinct biochemical and signaling mechanisms.
期刊介绍:
"Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets.
The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment.
In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.