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Y192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection
| Content Provider | MDPI |
|---|---|
| Author | Matthias, Kästle Merten, Camilla Hartig, Roland Plaza-Sirvent, Carlos Schmitz, Ingo Bommhardt, Ursula Schraven, Burkhart Simeoni, Luca |
| Copyright Year | 2022 |
| Description | 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 $Ca^{2+}$ influx and phosphorylation of Erk1/2 are impaired. Accordingly, positive and negative selections are blocked in $Lck^{Y192E}$ 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. |
| Starting Page | 7271 |
| e-ISSN | 14220067 |
| DOI | 10.3390/ijms23137271 |
| Journal | International Journal of Molecular Sciences |
| Issue Number | 13 |
| Volume Number | 23 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-06-30 |
| Access Restriction | Open |
| Subject Keyword | International Journal of Molecular Sciences Immunology Lck T-cell Development Thymic Selection Tcr Signaling Lcky192 |
| Content Type | Text |
| Resource Type | Article |
