Non-canonical binding of the LCK SH3 domain to CD3[epsilon] redefines initiation of TCR signaling and enhances CAR function : = Non-canonical binding of LCK to the TCR

Abstract: Initiation of T cell antigen receptor (TCR) signaling involves phosphorylation of CD3 cytoplasmic tails by the tyrosine kinase Lck. How Lck is recruited to the TCR to initiate signaling is not well known. We report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain: the receptor kinase (RK) motif. The RK motif is accessible only upon TCR ligation, demonstrating how ligand binding leads to Lck recruitment. Binding of the Lck SH3 domain to the exposed RK motif resulted in local augmentation of Lck activity, CD3 phosphorylation, T cell activation and thymocyte development. Introducing the RK motif into a well-characterized 41BB-based chimeric antigen receptor enhanced its antitumor function in vitro and in vivo. Our findings underscore how a better understanding of the functioning of the TCR might promote rational improvement of chimeric antigen receptor design for the treatment of cancer

Angaben zum Objekt

• Weitere Titel: Non-canonical binding of LCK to the TCR
• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Ausgabe: Manuskriptversion
• Sprache: Englisch

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2021
• Urheber: Hartl, Frederike A ; Beck-García, Esmeralda ; Wössner, Nadine M. ; Flachsmann, Lea J. ; Velasco Cárdenas, Rubí Misol-Há ; Brandl, Simon M. ; Taromi, Sanaz ; Fiala, Gina Jasmin ; Morath, Anna ; Mishra, Pankaj ; Yousefi, Omid Sascha ; Zimmermann, Julia ; Hoefflin, Nico ; Köhn, Maja ; Wöhrl, Birgitta ; Zeiser, Robert ; Schweimer, Kristian ; Günther, Stefan ; Schamel, Wolfgang ; Minguet, Susana

Weitere Informationen

• DOI: 10.6094/UNIFR/194833
• URN: urn:nbn:de:bsz:25-freidok-1948332
• Rechteinformation: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Letzte Aktualisierung: 14.08.2025, 10:44 MESZ