Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection

• Published in: International journal of molecular sciences 2022-06, Vol.23 (13), p.7271
• Main Authors: Kästle, Matthias, Merten, Camilla, Hartig, Roland, Plaza-Sirvent, Carlos, Schmitz, Ingo, Bommhardt, Ursula, Schraven, Burkhart, Simeoni, Luca
• Format: Article
• Language: English
• Subjects: Lck; LckY192; T-cell development; TCR signaling; thymic selection
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23137271

Signaling via the TCR, which is initiated by the Src-family tyrosine kinase Lck, is crucial for the determination of cell fates in the thymus. Because of its pivotal role, ablation of Lck results in a profound block of T-cell development. Here, we show that, in addition to its well-known function in the initiation of TCR signaling, Lck also acts at a more downstream level. This novel function of Lck is determined by the tyrosine residue (Y192) located in its SH2 domain. Thymocytes from knock-in mice expressing a phosphomimetic Y192E mutant of Lck initiate TCR signaling upon CD3 cross-linking up to the level of PLC-γ1 phosphorylation. However, the activation of downstream pathways including Ca2+ influx and phosphorylation of Erk1/2 are impaired. Accordingly, positive and negative selections are blocked in LckY192E knock-in mice. Collectively, our data indicate that Lck has a novel function downstream of PLCγ-1 in the regulation of thymocyte differentiation and selection.