{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:13:11Z","timestamp":1791655991742,"version":"4.3.4"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"28","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,7,14]]},"abstract":"<jats:p>\n                    RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF\/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of\n                    <jats:italic>RIT1<\/jats:italic>\n                    mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adf4766","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T13:58:16Z","timestamp":1689343096000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":30,"title":["RAS-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome\u2013associated cardiac hypertrophy"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6208-6944","authenticated-orcid":true,"given":"Antonio","family":"Cuevas-Navarro","sequence":"first","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San\u00a0Francisco, San\u00a0Francisco, CA 94158, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6619-7120","authenticated-orcid":true,"given":"Frank","family":"McCormick","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San\u00a0Francisco, San\u00a0Francisco, CA 94158, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8259-621X","authenticated-orcid":true,"given":"Andrew G.","family":"Stephen","sequence":"additional","affiliation":[{"name":"NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4972-4347","authenticated-orcid":true,"given":"Pau","family":"Castel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular 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