Lymphocyte-specific protein tyrosine kinase (LCK) (LCK)

Lymphocyte-specific protein tyrosine kinase (LCK) is a 56 kDa non-receptor tyrosine kinase of the Src family, primarily expressed in T-lymphocytes and natural killer (NK) cells (UniProt: P06239). It plays a fundamental role in the initiation of T-cell receptor (TCR) signaling by phosphorylating the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 complex and the zeta-chain upon antigen recognition (PubMed: 25533380). The target name "T-cell–mediated cytotoxicity in the presence of ponatinib" refers to a phenotypic assay context where the multi-kinase inhibitor ponatinib exerts potent off-target inhibition of LCK (PubMed: 28533415). By blocking LCK activity, ponatinib suppresses the downstream signaling required for T-cell activation, proliferation, and effector functions, including the ability of T-cells to kill target cells (PubMed: 30254133). This molecular interaction is clinically significant as it can lead to drug-induced immunosuppression or interfere with the efficacy of T-cell-based immunotherapies such as bispecific T-cell engagers (BiTEs) or CAR-T cells (NIH: PubChem CID 24826799).

Other names

p56lckLSKT cell-specific protein-tyrosine kinaseT-cell–mediated cytotoxicity (phenotypic target)T-cell–mediated cytotoxicity in the presence of ponatinib

Ponatinib acts as an ATP-competitive inhibitor of the LCK kinase domain, preventing the phosphorylation of TCR-associated ITAMs and downstream signaling molecules like ZAP-70, thereby suppressing T-cell activation and cytotoxicity (PubMed: 28533415).