Type of PaperY192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection
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...
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| Veröffentlicht in: | International journal of molecular sciences 2022-07, Vol.23 (13), p.7271 |
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| creator | Kästle, Matthias Merten, Camilla Hartig, Roland Plaza-Sirvent, Carlos Schmitz, Ingo Bommhardt, Ursula Burkhart Schraven Simeoni, Luca |
| 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 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. |
| doi_str_mv | 10.3390/ijms23137271 |
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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.</description><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms23137271</identifier><identifier>PMID: 35806279</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Ablation ; Calcium influx ; Calcium ions ; CD3 antigen ; Crosslinking ; Domains ; Extracellular signal-regulated kinase ; Hypotheses ; Kinases ; Lck protein ; Lymphocytes ; Lymphocytes T ; Mutation ; Peptides ; Phosphorylation ; Protein-tyrosine kinase ; T cell receptors ; Thymocytes ; Thymus ; Thymus gland ; Transgenic animals ; Tyrosine</subject><ispartof>International journal of molecular sciences, 2022-07, Vol.23 (13), p.7271</ispartof><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. 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| subjects | Ablation Calcium influx Calcium ions CD3 antigen Crosslinking Domains Extracellular signal-regulated kinase Hypotheses Kinases Lck protein Lymphocytes Lymphocytes T Mutation Peptides Phosphorylation Protein-tyrosine kinase T cell receptors Thymocytes Thymus Thymus gland Transgenic animals Tyrosine |
| title | Type of PaperY192 within the SH2 Domain of Lck Regulates TCR Signaling Downstream of PLC-γ1 and Thymic Selection |
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