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We recover this directivity from molecular dynamics (MD) of transmembrane\u2013juxtamembrane (TM\u2013JM) dimers of receptor tyrosine kinases EGFR and FGFR3. Coupling is detected with a Bayesian network framework (CASCADE); its direction is measured with PERI (Phase-plane Estimation of Rotational Irreversibility) as the net phase-plane circulation, validated on synthetic data, and resolved at 0.1 ns. Direction is summarized as the TM\u2192JM directed-mass fraction f+ (0.5 = balanced) via a hierarchical Bayesian model. The activating TM mutants EGFR L658Q and FGFR3 A391E are TM\u2192JM (posterior probabilities: 0.95 and 0.99); fluid wild-type EGFR leans the same way (0.93), in agreement with its experimentally reported constitutive activity in fluid but not ordered bilayers; the ligand-dependent ordered wild-type is balanced (0.45); and an activating mutation raises the TM\u2192JM bias above the ordered wild-type with probability 0.94. The directivity thus tracks the measured activity state of the receptor, distinguishing signaling-competent from ligand-dependent RTK dimers by a property not apparent from structure alone.<\/jats:p>","DOI":"10.1021\/jacs.6c10487","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:01:59Z","timestamp":1790704919000},"page":"43114-43122","source":"Crossref","is-referenced-by-count":0,"title":["A Directed TM\u2192JM\nCoupling in Receptor Tyrosine\nKinase Dimers, Set by Activating Mutations and the Membrane Environment"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9156-8655","authenticated-orcid":true,"given":"Takeshi","family":"Sato","sequence":"first","affiliation":[{"name":"Kyoto Pharmaceutical University , ,","place":["Kyoto, Japan, 607-8414"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8775-1775","authenticated-orcid":true,"given":"Hiroko","family":"Tamagaki-Asahina","sequence":"additional","affiliation":[{"name":"Kyoto Pharmaceutical University , ,","place":["Kyoto, Japan, 607-8414"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"issue":"7","key":"2026101414092391600_cit1","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1016\/j.cell.2010.06.011","article-title":"Cell signaling by receptor tyrosine kinases","volume":"141","author":"Lemmon","year":"2010","journal-title":"Cell"},{"issue":"3","key":"2026101414092391600_cit2","doi-asserted-by":"publisher","first-page":"a008912","DOI":"10.1101\/cshperspect.a008912","article-title":"Receptor tyrosine\nkinases: legacy of the first two decades","volume":"6","author":"Schlessinger","year":"2014","journal-title":"Cold\nSpring Harbor Perspect. 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