{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:15:47Z","timestamp":1788066947812,"version":"build-2784847793"},"reference-count":88,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["AH 92\/8-1"],"award-info":[{"award-number":["AH 92\/8-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"award":["AH 92\/8-1"],"award-info":[{"award-number":["AH 92\/8-1"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson\u2019s disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. Here, we demonstrate that RIT1 differs from classical RAS in GTPase cycling. Unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis under cell-free conditions. These results imply that RIT1 may depend on regulatory mechanisms that differ from those of classical RAS proteins. However, the relevant physiological regulators remain unknown. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions. In this transient overexpression screening system, however, these mutations had only a modest effect on the canonical MAPK, PI3K\/AKT, and JNK signaling pathways in HEK293T overexpression experiments. This suggests the existence of additional context-specific effectors and regulatory factors. We demonstrate that RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension. The KRLK-containing region contributes to the binding of phosphatidylserine and phosphoinositides. Charge-reversal mutations disrupt lipid interactions and liposome binding, supporting the functional importance of this region. In a reconstituted liposome system, galectin-3 and LZTR1, but not galectin-1, reduced the interaction of GDP-loaded RIT1 and RIT2 with liposomes. These results suggest that accessory proteins may influence RIT membrane interactions. However, their cellular relevance requires further validation. Together, our findings provide biochemical insights into RIT GTPase regulation and its interactions with membrane lipids under cell-free conditions.<\/jats:p>","DOI":"10.3390\/cells15171567","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T18:33:52Z","timestamp":1787942032000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["New Biochemical Insights into RIT GTPases Regulation and Membrane Interactions"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3340-586X","authenticated-orcid":false,"given":"Amin","family":"Mirzaiebadizi","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0689-7926","authenticated-orcid":false,"given":"Farhad","family":"Bazgir","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5786-8992","authenticated-orcid":false,"given":"Niloufar","family":"Mosaddeghzadeh","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4653-7263","authenticated-orcid":false,"given":"Silke","family":"Pudewell","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7842-6998","authenticated-orcid":false,"given":"Neda S.","family":"Kazemein Jasemi","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radovan","family":"Dvorsky","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2034-8894","authenticated-orcid":false,"given":"Mohammad R.","family":"Ahmadian","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University D\u00fcsseldorf, Universit\u00e4tsstrasse 1, Building 22.03, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1080\/10409238.2018.1431605","article-title":"Structural fingerprints, interactions, and signaling networks of RAS family proteins beyond RAS isoforms","volume":"53","author":"Haghighi","year":"2018","journal-title":"Crit. 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