{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:39:26Z","timestamp":1792669166081,"version":"4.5.0"},"reference-count":142,"publisher":"AIP Publishing","issue":"16","license":[{"start":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:00:00Z","timestamp":1792627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["HHSN261201500003I"],"award-info":[{"award-number":["HHSN261201500003I"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pubs.aip.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,28]]},"abstract":"<jats:p>Here, we review the active roles and mechanisms of the plasma membrane and phospholipids in peripheral membrane proteins and lipid-anchored membrane proteins, focusing on the Ras-Raf-PI3K-PTEN signaling network. Data for some phospholipids are scant (or non-existent), whereas for others the mechanistic details are often incomplete\u2014likely due to the challenging nature of membrane dynamics. Identification of the direct, specific interactions of the phospholipids with proteins is often lacking; instead, these lipids are frequently described as creating a negatively charged lipid environment, transiently interacting with proteins. To clarify these elusive yet cardinal mechanisms, we contrast lipid-coupled conformational changes with macroscopic bilayer effects\u2014including altered dimensionality, curvature, and lateral pressure\u2014that collectively modulate protein function by shifting conformational ensembles and local concentration. These lead us to consider specific lipid-binding allostery, membrane-property-mediated conformational coupling, recruitment and orientation effects, and proximity, avidity, and clustering effects. While specific lipid\u2013protein interactions are often transient, both components serve vital active roles in protein function. This is reinforced by distinguishing between canonical, site-specific allosteric regulation and broader membrane-mediated phenomena. Pharmacology at the membrane has been challenging; direct specific lipid-binding allostery is complicated by the often-transient membrane lipid\u2013protein interactions. Coupled with macroscopic bilayer effects, such pharmacology can elicit toxic side-effects. Specifically targeting the regulation of membrane-associated proteins, autoinhibition and activation, may fare better in the clinic. The Ras-Raf-PI3K-PTEN signaling network, which is anchored and controlled by membrane interaction and can be viewed as the heart of cell proliferation, is an especially relevant system to explore.<\/jats:p>","DOI":"10.1063\/5.0354338","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:50:19Z","timestamp":1792666219000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Allostery in the Ras-Raf-PI3K-PTEN signaling network at the membrane: Implications for drug discovery"],"prefix":"10.1063","volume":"165","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8115-6415","authenticated-orcid":false,"given":"Ruth","family":"Nussinov","sequence":"first","affiliation":[{"name":"Biophysics and Computational Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute 1 , Frederick, Maryland 21702,","place":["USA"]},{"name":"Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University 2 , Tel Aviv 69978,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9402-4051","authenticated-orcid":false,"given":"Hyunbum","family":"Jang","sequence":"additional","affiliation":[{"name":"Biophysics and Computational Biology Section, Frederick National Laboratory for Cancer Research in the Cancer Innovation Laboratory, National Cancer Institute 1 , Frederick, Maryland 21702,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2026,10,22]]},"reference":[{"key":"2026102206501040800_c1","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1126\/science.1749933","article-title":"The energy landscapes and motions of proteins","volume":"254","year":"1991","journal-title":"Science"},{"key":"2026102206501040800_c2","doi-asserted-by":"publisher","first-page":"169044","DOI":"10.1016\/j.jmb.2025.169044","article-title":"Pioneer in molecular biology: Conformational ensembles in molecular recognition, allostery, and cell function","volume":"437","year":"2025","journal-title":"J.\u00a0Mol. Biol."},{"key":"2026102206501040800_c3","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1039\/d3cb00114h","article-title":"Protein conformational ensembles in function: Roles and mechanisms","volume":"4","year":"2023","journal-title":"RSC Chem. Biol."},{"key":"2026102206501040800_c4","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1038\/nchembio.232","article-title":"The role of dynamic conformational ensembles in biomolecular recognition","volume":"5","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"2026102206501040800_c5","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/978-3-319-02970-2_3","article-title":"Understanding protein dynamics using conformational ensembles","volume":"805","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"2026102206501040800_c6","doi-asserted-by":"publisher","first-page":"6516","DOI":"10.1021\/acs.chemrev.5b00562","article-title":"Protein ensembles: How does nature harness thermodynamic fluctuations for life? The diverse functional roles of conformational ensembles in the cell","volume":"116","year":"2016","journal-title":"Chem. Rev."},{"key":"2026102206501040800_c7","doi-asserted-by":"publisher","first-page":"19346","DOI":"10.1073\/pnas.0906966106","article-title":"Conformational selection and induced fit mechanism underlie specificity in noncovalent interactions with ubiquitin","volume":"106","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c8","doi-asserted-by":"publisher","first-page":"e1002301","DOI":"10.1371\/journal.pcbi.1002301","article-title":"Coherent conformational degrees of freedom as a structural basis for allosteric communication","volume":"7","year":"2011","journal-title":"PLoS Comput. Biol."},{"key":"2026102206501040800_c9","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.str.2019.01.003","article-title":"Allostery in its many disguises: From theory to applications","volume":"27","year":"2019","journal-title":"Structure"},{"key":"2026102206501040800_c10","doi-asserted-by":"publisher","first-page":"MSB4100063","DOI":"10.1038\/msb4100063","article-title":"Residues crucial for maintaining short paths in network communication mediate signaling in proteins","volume":"2","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"2026102206501040800_c11","doi-asserted-by":"publisher","first-page":"W249","DOI":"10.1093\/nar\/gkt284","article-title":"MCPath: Monte Carlo path generation approach to predict likely allosteric pathways and functional residues","volume":"41","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"2026102206501040800_c12","doi-asserted-by":"publisher","first-page":"169326","DOI":"10.1016\/j.jmb.2025.169326","article-title":"Deciphering allosteric disease mutations through intrinsic dynamics","volume":"437","year":"2025","journal-title":"J.\u00a0Mol. Biol."},{"key":"2026102206501040800_c13","doi-asserted-by":"publisher","first-page":"2757","DOI":"10.1021\/jacs.3c12494","article-title":"Modulation of allostery with multiple mechanisms by hotspot mutations in TetR","volume":"146","year":"2024","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"2026102206501040800_c14","doi-asserted-by":"publisher","first-page":"e1003394","DOI":"10.1371\/journal.pcbi.1003394","article-title":"A unified view of \u201chow allostery works\u201d","volume":"10","year":"2014","journal-title":"PLoS Comput. Biol."},{"key":"2026102206501040800_c15","doi-asserted-by":"publisher","first-page":"15177","DOI":"10.1021\/ja304672h","article-title":"Rational design of allosteric inhibitors and activators using the population-shift model: In vitro validation and application to an artificial biosensor","volume":"134","year":"2012","journal-title":"J.\u00a0Am. Chem. Soc."},{"key":"2026102206501040800_c16","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.coph.2010.09.002","article-title":"Allostery and population shift in drug discovery","volume":"10","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"2026102206501040800_c17","doi-asserted-by":"publisher","first-page":"6503","DOI":"10.1021\/acs.chemrev.5b00590","article-title":"Protein allostery and conformational dynamics","volume":"116","year":"2016","journal-title":"Chem. Rev."},{"key":"2026102206501040800_c18","doi-asserted-by":"publisher","first-page":"e5","DOI":"10.1017\/s0033583524000209","article-title":"Allostery","volume":"58","year":"2025","journal-title":"Q. Rev. Biophys."},{"key":"2026102206501040800_c19","doi-asserted-by":"publisher","first-page":"1954","DOI":"10.1016\/j.bpj.2019.10.002","article-title":"Mechanics of allostery: Contrasting the induced fit and population shift scenarios","volume":"117","year":"2019","journal-title":"Biophys. J."},{"key":"2026102206501040800_c20","doi-asserted-by":"publisher","first-page":"e1004966","DOI":"10.1371\/journal.pcbi.1004966","article-title":"Allostery: An overview of its history, concepts, methods, and applications","volume":"12","year":"2016","journal-title":"PLoS Comput. Biol."},{"key":"2026102206501040800_c21","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.sbi.2010.10.007","article-title":"Protein dynamics and allostery: An NMR view","volume":"21","year":"2011","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026102206501040800_c22","doi-asserted-by":"publisher","first-page":"021097","DOI":"10.1103\/wv2k-676p","article-title":"Allosteric lever: Toward a principle of specific allosteric response","volume":"15","year":"2025","journal-title":"Phys. Rev. X"},{"key":"2026102206501040800_c23","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/nrm.2017.138","article-title":"Understanding the diversity of membrane lipid composition","volume":"19","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026102206501040800_c24","volume-title":"The Cell: A Molecular Approach","year":"2000","edition":"2"},{"key":"2026102206501040800_c25","doi-asserted-by":"publisher","first-page":"103190","DOI":"10.1016\/j.sbi.2025.103190","article-title":"The current understanding of KRAS oligomerization on membranes","volume":"96","year":"2026","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026102206501040800_c26","doi-asserted-by":"publisher","first-page":"111207","DOI":"10.1016\/j.jbc.2026.111207","article-title":"A new functional assay reveals that membrane binding is critical for overactivation of the phosphoinositide 3-kinase H1047R mutant","volume":"302","year":"2026","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c27","doi-asserted-by":"publisher","first-page":"pgad126","DOI":"10.1093\/pnasnexus\/pgad126","article-title":"Allosteric modulation of integral protein activity by differential stress in asymmetric membranes","volume":"2","year":"2023","journal-title":"PNAS Nexus"},{"key":"2026102206501040800_c28","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1146\/annurev-biophys-090721-072718","article-title":"Lipid-protein interactions in plasma membrane organization and function","volume":"51","year":"2022","journal-title":"Annu. Rev. Biophys."},{"key":"2026102206501040800_c29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/s0009-3084(99)00052-3","article-title":"The electrostatics of lipid surfaces","volume":"101","year":"1999","journal-title":"Chem. Phys. Lipids"},{"key":"2026102206501040800_c30","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1073\/pnas.1719813115","article-title":"Allostery revealed within lipid binding events to membrane proteins","volume":"115","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c31","doi-asserted-by":"publisher","first-page":"184531","DOI":"10.1016\/j.bbamem.2026.184531","article-title":"Ten questions on membrane biophysics","volume":"1868","year":"2026","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"2026102206501040800_c32","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.3390\/biom11101439","article-title":"Lipid profiles of RAS nanoclusters regulate RAS function","volume":"11","year":"2021","journal-title":"Biomolecules"},{"key":"2026102206501040800_c33","doi-asserted-by":"publisher","first-page":"5379","DOI":"10.1021\/acs.jproteome.1c00550","article-title":"Cholesterol regulates the tumor adaptive resistance to MAPK pathway inhibition","volume":"20","year":"2021","journal-title":"J.\u00a0Proteome Res."},{"key":"2026102206501040800_c34","doi-asserted-by":"publisher","first-page":"1306483","DOI":"10.3389\/fmolb.2023.1306483","article-title":"Regulatory mechanisms triggered by enzyme interactions with lipid membrane surfaces","volume":"10","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"2026102206501040800_c35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/B978-0-12-417027-8.00003-9","article-title":"Membrane protein dynamics and functional implications in Mammalian cells","volume":"72","year":"2013","journal-title":"Curr. Top. Membr."},{"key":"2026102206501040800_c36","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.semcancer.2018.02.009","article-title":"Oncogenic KRas mobility in the membrane and signaling response","volume":"54","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"2026102206501040800_c37","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.semcancer.2018.01.002","article-title":"Is nanoclustering essential for all oncogenic KRas pathways? Can it explain why wild-type KRas can inhibit its oncogenic variant?","volume":"54","year":"2019","journal-title":"Semin. Cancer Biol."},{"key":"2026102206501040800_c38","doi-asserted-by":"publisher","first-page":"18","DOI":"10.3389\/fpls.2014.00018","article-title":"Membrane microdomains: From seeing to understanding","volume":"5","year":"2014","journal-title":"Front. Plant Sci."},{"key":"2026102206501040800_c39","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/nsmb.1844","article-title":"Molecular mechanisms in signal transduction at the membrane","volume":"17","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2026102206501040800_c40","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41580-022-00524-4","article-title":"Regulation of membrane protein structure and function by their lipid nano-environment","volume":"24","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2026102206501040800_c41","doi-asserted-by":"publisher","first-page":"5775","DOI":"10.1021\/acs.chemrev.8b00451","article-title":"Emerging diversity in lipid-protein interactions","volume":"119","year":"2019","journal-title":"Chem. Rev."},{"key":"2026102206501040800_c42","doi-asserted-by":"publisher","first-page":"9782","DOI":"10.1021\/bi301332v","article-title":"Curvature forces in membrane lipid-protein interactions","volume":"51","year":"2012","journal-title":"Biochemistry"},{"key":"2026102206501040800_c43","doi-asserted-by":"publisher","first-page":"6086","DOI":"10.1021\/acs.chemrev.8b00608","article-title":"Characterization of lipid-protein interactions and lipid-mediated modulation of membrane protein function through molecular simulation","volume":"119","year":"2019","journal-title":"Chem. Rev."},{"key":"2026102206501040800_c44","doi-asserted-by":"publisher","first-page":"24325","DOI":"10.1039\/d5nr02822a","article-title":"The significance of lipid membrane curvature and lipid order for nano-C60 uptake","volume":"17","year":"2025","journal-title":"Nanoscale"},{"key":"2026102206501040800_c45","doi-asserted-by":"publisher","first-page":"2162","DOI":"10.1038\/s41467-020-15741-8","article-title":"Lipid-protein interactions modulate the conformational equilibrium of a potassium channel","volume":"11","year":"2020","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c46","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1016\/j.bpj.2025.07.019","article-title":"The membrane properties determine protein function: A new aspect of allosteric modulation","volume":"124","year":"2025","journal-title":"Biophys. J."},{"key":"2026102206501040800_c47","doi-asserted-by":"publisher","first-page":"7709","DOI":"10.1021\/acs.jcim.4c01392","article-title":"Capturing autoinhibited PDK1 reveals the linker\u2019s regulatory role, informing innovative inhibitor design","volume":"64","year":"2024","journal-title":"J.\u00a0Chem. Inf. Model."},{"key":"2026102206501040800_c48","doi-asserted-by":"publisher","first-page":"e70420","DOI":"10.1002\/pro.70420","article-title":"The structural heterogeneity of AKT autoinhibition","volume":"35","year":"2026","journal-title":"Protein Sci."},{"key":"2026102206501040800_c49","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1038\/cr.2014.57","article-title":"Akt: A new activation mechanism","volume":"24","year":"2014","journal-title":"Cell Res."},{"key":"2026102206501040800_c50","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1016\/j.cell.2018.07.003","article-title":"Akt kinase activation mechanisms revealed using protein semisynthesis","volume":"174","year":"2018","journal-title":"Cell"},{"key":"2026102206501040800_c51","doi-asserted-by":"publisher","first-page":"5443","DOI":"10.1007\/s11030-025-11132-7","article-title":"Structural insights of AKT and its activation mechanism for drug development","volume":"29","year":"2025","journal-title":"Mol. Divers"},{"key":"2026102206501040800_c52","doi-asserted-by":"publisher","first-page":"e2101496118","DOI":"10.1073\/pnas.2101496118","article-title":"Structure of autoinhibited Akt1 reveals mechanism of PIP3-mediated activation","volume":"118","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c53","doi-asserted-by":"publisher","first-page":"67","DOI":"10.3390\/biom9020067","article-title":"Getting the Akt together: Guiding intracellular Akt activity by PI3K","volume":"9","year":"2019","journal-title":"Biomolecules"},{"key":"2026102206501040800_c54","doi-asserted-by":"publisher","first-page":"1874","DOI":"10.1038\/s41467-022-29368-4","article-title":"Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation","volume":"13","year":"2022","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c55","doi-asserted-by":"publisher","first-page":"105224","DOI":"10.1016\/j.jbc.2023.105224","article-title":"PI3K signaling through a biochemical systems lens","volume":"299","year":"2023","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c56","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1039\/c8sc04498h","article-title":"The mechanism of PI3K\u03b1 activation at the atomic level","volume":"10","year":"2019","journal-title":"Chem. Sci."},{"key":"2026102206501040800_c57","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3390\/cancers17010077","article-title":"Molecular basis of oncogenic PI3K proteins","volume":"17","year":"2024","journal-title":"Cancers"},{"key":"2026102206501040800_c58","doi-asserted-by":"publisher","first-page":"2858","DOI":"10.1016\/j.molcel.2026.06.010","article-title":"Structures of the PI3K\u03b1\/KRas complex on lipid bilayers reveal molecular mechanisms of PI3K\u03b1 activation","volume":"86","year":"2026","journal-title":"Mol. Cell"},{"key":"2026102206501040800_c59","doi-asserted-by":"publisher","first-page":"e2319491121","DOI":"10.1073\/pnas.2319491121","article-title":"Membrane localization accelerates association under conditions relevant to cellular signaling","volume":"121","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c60","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41467-023-35789-6","article-title":"Oncogenic mutations of PIK3CA lead to increased membrane recruitment driven by reorientation of the ABD, p85 and C-terminus","volume":"14","year":"2023","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c61","doi-asserted-by":"publisher","first-page":"5607","DOI":"10.1016\/j.csbj.2022.10.007","article-title":"The orchestrated signaling by PI3K\u03b1 and PTEN at the membrane interface","volume":"20","year":"2022","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2026102206501040800_c62","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s42004-025-01714-9","article-title":"Structural and allosteric effects of the membrane-bound PI3K\u03b1 H1047R mutation and opportunities for drug discovery","volume":"8","year":"2025","journal-title":"Commun. Chem."},{"key":"2026102206501040800_c63","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/s42004-026-01906-x","article-title":"Oncogenic PI3K\u03b1 variants reveal graded conformational spectrum with mutation-specific cryptic pockets","volume":"9","year":"2026","journal-title":"Commun. Chem."},{"key":"2026102206501040800_c64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2142\/biophysico.13.0_1","article-title":"Switching of the positive feedback for RAS activation by a concerted function of SOS membrane association domains","volume":"13","year":"2016","journal-title":"Biophys. Physicobiol."},{"key":"2026102206501040800_c65","doi-asserted-by":"publisher","first-page":"14213","DOI":"10.1073\/pnas.1301883110","article-title":"Structural basis for membrane recruitment and allosteric activation of cytohesin family Arf GTPase exchange factors","volume":"110","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c66","doi-asserted-by":"publisher","first-page":"e70383","DOI":"10.1002\/pro.70383","article-title":"Membrane-forming phospholipids allosterically modulate native-state prolyl isomerization in a CNG channel","volume":"34","year":"2025","journal-title":"Protein Sci."},{"key":"2026102206501040800_c67","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1038\/s41467-017-02397-0","article-title":"Allosteric modulation of protein-protein interactions by individual lipid binding events","volume":"8","year":"2017","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c68","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1016\/j.devcel.2023.06.001","article-title":"The membrane surface as a platform that organizes cellular and biochemical processes","volume":"58","year":"2023","journal-title":"Dev. Cell"},{"key":"2026102206501040800_c69","doi-asserted-by":"publisher","first-page":"33617","DOI":"10.1074\/jbc.c300296200","article-title":"Allosteric activation of PTEN phosphatase by phosphatidylinositol 4,5-bisphosphate","volume":"278","year":"2003","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c70","doi-asserted-by":"publisher","first-page":"102438","DOI":"10.1016\/j.isci.2021.102438","article-title":"The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane","volume":"24","year":"2021","journal-title":"iScience"},{"key":"2026102206501040800_c71","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1016\/j.molcel.2016.12.028","article-title":"PI(3,4,5)P3 engagement restricts Akt activity to cellular membranes","volume":"65","year":"2017","journal-title":"Mol. Cell"},{"key":"2026102206501040800_c72","doi-asserted-by":"publisher","first-page":"5023","DOI":"10.1016\/j.jmb.2020.03.024","article-title":"Membrane lipids assist catalysis by CTP: Phosphocholine cytidylyltransferase","volume":"432","year":"2020","journal-title":"J.\u00a0Mol. Biol."},{"key":"2026102206501040800_c73","doi-asserted-by":"publisher","first-page":"101873","DOI":"10.1016\/j.jbc.2022.101873","article-title":"Allosteric regulation by membranes and hydrophobic subsites in phospholipase A(2) enzymes determine their substrate specificity","volume":"298","year":"2022","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c74","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1016\/s0968-0004(00)01625-x","article-title":"Regulation of CTP:phosphocholine cytidylyltransferase by amphitropism and relocalization","volume":"25","year":"2000","journal-title":"Trends Biochem. Sci."},{"key":"2026102206501040800_c75","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.plipres.2015.07.001","article-title":"CTP:phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis","volume":"59","year":"2015","journal-title":"Prog. Lipid Res."},{"key":"2026102206501040800_c76","doi-asserted-by":"publisher","first-page":"9917","DOI":"10.1021\/bi960397c","article-title":"Lipid regulation of CTP: Phosphocholine cytidylyltransferase: Electrostatic, hydrophobic, and synergistic interactions of anionic phospholipids and diacylglycerol","volume":"35","year":"1996","journal-title":"Biochemistry"},{"key":"2026102206501040800_c77","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1021\/bi002140r","article-title":"Lipid activation of CTP: Phosphocholine cytidylyltransferase alpha: Characterization and identification of a second activation domain","volume":"40","year":"2001","journal-title":"Biochemistry"},{"key":"2026102206501040800_c78","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/j.sbi.2011.07.006","article-title":"Regulation of protein kinases by lipids","volume":"21","year":"2011","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2026102206501040800_c79","doi-asserted-by":"publisher","first-page":"105022","DOI":"10.1016\/j.jbc.2023.105022","article-title":"Mechanisms controlling membrane recruitment and activation of the autoinhibited SHIP1 inositol 5-phosphatase","volume":"299","year":"2023","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c80","doi-asserted-by":"publisher","first-page":"e2528109123","DOI":"10.1073\/pnas.2528109123","article-title":"Two-step mechanism of Bruton\u2019s tyrosine kinase membrane recruitment and activation","volume":"123","year":"2026","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c81","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1158\/0008-5472.can-20-0911","article-title":"PI3K driver mutations: A biophysical membrane-centric perspective","volume":"81","year":"2021","journal-title":"Cancer Res."},{"key":"2026102206501040800_c82","doi-asserted-by":"publisher","first-page":"12021","DOI":"10.1039\/c9cp00101h","article-title":"The structural basis for Ras activation of PI3K\u03b1 lipid kinase","volume":"21","year":"2019","journal-title":"Phys. Chem. Chem. Phys."},{"key":"2026102206501040800_c83","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1021\/acs.chemrev.6b00750","article-title":"Protein lipidation: Occurrence, mechanisms, biological functions, and enabling technologies","volume":"118","year":"2018","journal-title":"Chem. Rev."},{"key":"2026102206501040800_c84","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1038\/s41586-019-1660-y","article-title":"Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes","volume":"575","year":"2019","journal-title":"Nature"},{"key":"2026102206501040800_c85","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/s41467-022-28084-3","article-title":"Structural insights into the BRAF monomer-to-dimer transition mediated by RAS binding","volume":"13","year":"2022","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c86","doi-asserted-by":"publisher","first-page":"RP88836","DOI":"10.7554\/eLife.88836","article-title":"Unveiling the domain-specific and RAS isoform-specific details of BRAF kinase regulation","volume":"12","year":"2023","journal-title":"eLife"},{"key":"2026102206501040800_c87","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1038\/s41467-021-21422-x","article-title":"KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation","volume":"12","year":"2021","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c88","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1016\/j.str.2021.02.005","article-title":"B-Raf autoinhibition in the presence and absence of 14-3-3","volume":"29","year":"2021","journal-title":"Structure"},{"key":"2026102206501040800_c89","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1007\/s12551-021-00817-6","article-title":"Ras isoform-specific expression, chromatin accessibility, and signaling","volume":"13","year":"2021","journal-title":"Biophys. Rev."},{"key":"2026102206501040800_c90","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1042\/bst20253030","article-title":"RAS-membrane interaction and oligomerization: There is more than meets the eye","volume":"53","year":"2025","journal-title":"Biochem. Soc. Trans."},{"key":"2026102206501040800_c91","doi-asserted-by":"publisher","first-page":"e1136374","DOI":"10.1080\/21592799.2015.1136374","article-title":"Plasma membrane regulates Ras signaling networks","volume":"5","year":"2015","journal-title":"Cell. Logist."},{"key":"2026102206501040800_c92","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.cell.2017.06.009","article-title":"RAS proteins and their regulators in human disease","volume":"170","year":"2017","journal-title":"Cell"},{"key":"2026102206501040800_c93","doi-asserted-by":"publisher","first-page":"e202307121","DOI":"10.1083\/jcb.202307121","article-title":"RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains","volume":"223","year":"2024","journal-title":"J.\u00a0Cell Biol."},{"key":"2026102206501040800_c94","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1016\/j.bpj.2016.01.019","article-title":"Oncogenic K-Ras binds to an anionic membrane in two distinct orientations: A molecular dynamics analysis","volume":"110","year":"2016","journal-title":"Biophys. J."},{"key":"2026102206501040800_c95","doi-asserted-by":"publisher","first-page":"7068","DOI":"10.1074\/jbc.ra118.004021","article-title":"K-Ras G-domain binding with signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2): Membrane association, protein orientation, and function","volume":"294","year":"2019","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c96","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1021\/jacsau.1c00426","article-title":"Determinants of membrane orientation dynamics in lipid-modified small GTPases","volume":"2","year":"2022","journal-title":"JACS Au"},{"key":"2026102206501040800_c97","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s00232-021-00176-z","article-title":"Unveiling the dynamics of KRAS4b on lipid model membranes","volume":"254","year":"2021","journal-title":"J.\u00a0Membr. Biol."},{"key":"2026102206501040800_c98","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/tra.12541","article-title":"Deciphering lipid codes: K-Ras as a paradigm","volume":"19","year":"2018","journal-title":"Traffic"},{"key":"2026102206501040800_c99","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1016\/j.bpj.2016.01.020","article-title":"K-Ras at anionic membranes: Orientation, orientation\u2026Orientation. Recent simulations and experiments","volume":"110","year":"2016","journal-title":"Biophys. J."},{"key":"2026102206501040800_c100","doi-asserted-by":"publisher","first-page":"e201900343","DOI":"10.26508\/lsa.201900343","article-title":"Membrane curvature sensing of the lipid-anchored K-Ras small GTPase","volume":"2","year":"2019","journal-title":"Life Sci. Alliance"},{"key":"2026102206501040800_c101","doi-asserted-by":"publisher","first-page":"e2014605118","DOI":"10.1073\/pnas.2014605118","article-title":"The KRAS and other prenylated polybasic domain membrane anchors recognize phosphatidylserine acyl chain structure","volume":"118","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c102","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1042\/bst20230552","article-title":"Regulation of RAF family kinases: New insights from recent structural and biochemical studies","volume":"52","year":"2024","journal-title":"Biochem. Soc. Trans."},{"key":"2026102206501040800_c103","doi-asserted-by":"publisher","first-page":"a033746","DOI":"10.1101\/cshperspect.a033746","article-title":"Ras-mediated activation of the Raf family kinases","volume":"9","year":"2019","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"2026102206501040800_c104","doi-asserted-by":"publisher","first-page":"2593","DOI":"10.1038\/s41467-026-69437-6","article-title":"Positive cooperativity between RAS-binding and cysteine-rich domains regulates RAF membrane binding kinetics via lateral rebinding","volume":"17","year":"2026","journal-title":"Nat. Commun."},{"key":"2026102206501040800_c105","doi-asserted-by":"publisher","first-page":"e70419","DOI":"10.1002\/pro.70419","article-title":"The BRAF-specific region suppresses cysteine-rich domain-lipid interaction independently of canonical autoinhibition by the 14-3-3 dimer","volume":"35","year":"2026","journal-title":"Protein Sci."},{"key":"2026102206501040800_c106","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1038\/s41598-019-38770-w","article-title":"Three distinct regions of cRaf kinase domain interact with membrane","volume":"9","year":"2019","journal-title":"Sci. Rep."},{"key":"2026102206501040800_c107","doi-asserted-by":"publisher","first-page":"8312","DOI":"10.1073\/pnas.93.16.8312","article-title":"The solution structure of the Raf-1 cysteine-rich domain: A novel ras and phospholipid binding site","volume":"93","year":"1996","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c108","doi-asserted-by":"publisher","first-page":"3630","DOI":"10.1016\/j.bpj.2022.06.035","article-title":"Exploring CRD mobility during RAS\/RAF engagement at the membrane","volume":"121","year":"2022","journal-title":"Biophys. J."},{"key":"2026102206501040800_c109","doi-asserted-by":"publisher","first-page":"3862","DOI":"10.1038\/sj.onc.1202730","article-title":"Interactions of c-Raf-1 with phosphatidylserine and 14-3-3","volume":"18","year":"1999","journal-title":"Oncogene"},{"key":"2026102206501040800_c110","doi-asserted-by":"publisher","first-page":"8178","DOI":"10.1039\/d1sc00957e","article-title":"The Ras dimer structure","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2026102206501040800_c111","doi-asserted-by":"publisher","first-page":"e2015648118","DOI":"10.1073\/pnas.2015648118","article-title":"Raf promotes dimerization of the Ras G-domain with increased allosteric connections","volume":"118","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c112","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1016\/j.csbj.2020.03.018","article-title":"The quaternary assembly of KRas4B with Raf-1 at the membrane","volume":"18","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"2026102206501040800_c113","doi-asserted-by":"publisher","first-page":"1719","DOI":"10.1042\/bcj20160031","article-title":"Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers","volume":"473","year":"2016","journal-title":"Biochem. J."},{"key":"2026102206501040800_c114","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1016\/j.str.2015.04.019","article-title":"GTP-dependent K-Ras dimerization","volume":"23","year":"2015","journal-title":"Structure"},{"key":"2026102206501040800_c115","doi-asserted-by":"publisher","first-page":"15609","DOI":"10.1039\/d1sc03444h","article-title":"The mechanism of Raf activation through dimerization","volume":"12","year":"2021","journal-title":"Chem. Sci."},{"key":"2026102206501040800_c116","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1007\/s00018-010-0520-6","article-title":"Mechanistic principles of RAF kinase signaling","volume":"68","year":"2011","journal-title":"Cell. Mol. Life Sci."},{"key":"2026102206501040800_c117","doi-asserted-by":"publisher","first-page":"e2508169122","DOI":"10.1073\/pnas.2508169122","article-title":"An in vitro BRAF activation assay elucidates molecular mechanisms driving disassembly of the autoinhibited BRAF state","volume":"122","year":"2025","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c118","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s42003-024-05916-0","article-title":"Membrane lipids drive formation of KRAS4b-RAF1 RBDCRD nanoclusters on the membrane","volume":"7","year":"2024","journal-title":"Commun. Biol."},{"key":"2026102206501040800_c119","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K pathway in human disease","volume":"170","year":"2017","journal-title":"Cell"},{"key":"2026102206501040800_c120","doi-asserted-by":"publisher","first-page":"16996","DOI":"10.1073\/pnas.0908444106","article-title":"A frequent kinase domain mutation that changes the interaction between PI3K\u03b1 and the membrane","volume":"106","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c121","doi-asserted-by":"publisher","first-page":"13375","DOI":"10.1074\/jbc.273.22.13375","article-title":"The tumor suppressor, PTEN\/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate","volume":"273","year":"1998","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c122","doi-asserted-by":"publisher","first-page":"168354","DOI":"10.1016\/j.jmb.2023.168354","article-title":"Cancer and autism: How PTEN mutations degrade function at the membrane and isoform expression in the human brain","volume":"435","year":"2023","journal-title":"J.\u00a0Mol. Biol."},{"key":"2026102206501040800_c123","doi-asserted-by":"publisher","first-page":"11768","DOI":"10.1021\/bi035234k","article-title":"Lipid-induced conformational switch in the membrane binding domain of CTP:phosphocholine cytidylyltransferase: A circular dichroism study","volume":"42","year":"2003","journal-title":"Biochemistry"},{"key":"2026102206501040800_c124","doi-asserted-by":"publisher","first-page":"15531","DOI":"10.1074\/jbc.ra119.009850","article-title":"Remodeling of the interdomain allosteric linker upon membrane binding of CCTalpha pulls its active site close to the membrane surface","volume":"294","year":"2019","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c125","doi-asserted-by":"publisher","first-page":"8644","DOI":"10.1021\/acs.jpcb.9b05796","article-title":"Probing the conformational and energy landscapes of KRAS membrane orientation","volume":"123","year":"2019","journal-title":"J.\u00a0Phys. Chem. B"},{"key":"2026102206501040800_c126","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.bpj.2019.12.039","article-title":"The plasma membrane as a competitive inhibitor and positive allosteric modulator of KRas4B signaling","volume":"118","year":"2020","journal-title":"Biophys. J."},{"key":"2026102206501040800_c127","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1074\/jbc.m113.526970","article-title":"Structural basis for autoinhibition of CTP:phosphocholine cytidylyltransferase (CCT), the regulatory enzyme in phosphatidylcholine synthesis, by its membrane-binding amphipathic helix","volume":"289","year":"2014","journal-title":"J.\u00a0Biol. Chem."},{"key":"2026102206501040800_c128","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.trecan.2024.11.009","article-title":"KRAS inhibitors: Resistance drivers and combinatorial strategies","volume":"11","year":"2025","journal-title":"Trends Cancer"},{"key":"2026102206501040800_c129","doi-asserted-by":"publisher","first-page":"26556","DOI":"10.1073\/pnas.2017730117","article-title":"The hanging heart: How KRAS lures its prey to the membrane","volume":"117","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c130","doi-asserted-by":"publisher","first-page":"13193","DOI":"10.3390\/ijms222413193","article-title":"Past and future strategies to inhibit membrane localization of the KRAS oncogene","volume":"22","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2026102206501040800_c131","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1007\/s00249-012-0841-5","article-title":"The role of G-domain orientation and nucleotide state on the Ras isoform-specific membrane interaction","volume":"41","year":"2012","journal-title":"Eur. Biophys. J."},{"key":"2026102206501040800_c132","doi-asserted-by":"publisher","first-page":"6625","DOI":"10.1073\/pnas.1419895112","article-title":"Oncogenic and RASopathy-associated K-RAS mutations relieve membrane-dependent occlusion of the effector-binding site","volume":"112","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026102206501040800_c133","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.chembiol.2018.07.009","article-title":"Inhibition of K-RAS4B by a unique mechanism of action: Stabilizing membrane-dependent occlusion of the effector-binding site","volume":"25","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"2026102206501040800_c134","doi-asserted-by":"publisher","first-page":"2082","DOI":"10.1021\/acschembio.3c00413","article-title":"Direct modulators of K-Ras-Membrane interactions","volume":"18","year":"2023","journal-title":"ACS Chem. Biol."},{"key":"2026102206501040800_c135","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1080\/17568919.2024.2444865","article-title":"Targeting undruggable protein KRAS for cancer therapy: Novel opportunities and challenges","volume":"17","year":"2025","journal-title":"Future Med. Chem."},{"key":"2026102206501040800_c136","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1111\/cas.16441","article-title":"Mechanisms of resistance to KRAS inhibitors: Cancer cells\u2019 strategic use of normal cellular mechanisms to adapt","volume":"116","year":"2025","journal-title":"Cancer Sci."},{"key":"2026102206501040800_c137","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3390\/cancers13010151","article-title":"Mechanisms of resistance to KRAS(G12C) inhibitors","volume":"13","year":"2021","journal-title":"Cancers"},{"key":"2026102206501040800_c138","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/med.70035","article-title":"A comprehensive review of marketed KRAS inhibitors and degraders: Challenges and opportunities","volume":"46","year":"2026","journal-title":"Med. Res. Rev."},{"key":"2026102206501040800_c139","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s12943-024-02216-3","article-title":"Targeting KRAS: From metabolic regulation to cancer treatment","volume":"24","year":"2025","journal-title":"Mol. Cancer"},{"key":"2026102206501040800_c140","doi-asserted-by":"publisher","first-page":"e36161","DOI":"10.1016\/j.heliyon.2024.e36161","article-title":"Insight into structural dynamics involved in activation mechanism of full length KRAS wild type and P-loop mutants","volume":"10","year":"2024","journal-title":"Heliyon"},{"key":"2026102206501040800_c141","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1158\/2159-8290.cd-23-0944","article-title":"Discovery and clinical proof-of-concept of RLY-2608, a first-in-class mutant-selective allosteric PI3Kalpha inhibitor that decouples antitumor activity from hyperinsulinemia","volume":"14","year":"2024","journal-title":"Cancer Discovery"},{"key":"2026102206501040800_c142","doi-asserted-by":"publisher","first-page":"e2312898","DOI":"10.1002\/adma.202312898","article-title":"Phospholipid membranes as chemically and functionally tunable materials","volume":"36","year":"2024","journal-title":"Adv. Mater."}],"container-title":["The Journal of Chemical Physics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0354338\/21178762\/161001_1_5.0354338.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.aip.org\/aip\/jcp\/article-pdf\/doi\/10.1063\/5.0354338\/21178762\/161001_1_5.0354338.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:50:21Z","timestamp":1792666221000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.aip.org\/jcp\/article\/165\/16\/161001\/3407131\/Allostery-in-the-Ras-Raf-PI3K-PTEN-signaling"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,22]]},"references-count":142,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2026,10,28]]}},"URL":"https:\/\/doi.org\/10.1063\/5.0354338","relation":{},"ISSN":["0021-9606","1089-7690"],"issn-type":[{"value":"0021-9606","type":"print"},{"value":"1089-7690","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,10,28]]},"published":{"date-parts":[[2026,10,22]]},"article-number":"161001"}}