Tyrosine-protein kinase Lck (Lck)

Tyrosine-protein kinase Lck is a non-receptor tyrosine kinase of the Src family, primarily expressed in T lymphocytes and natural killer (NK) cells [1, 2]. It is essential for the initiation of T-cell receptor (TCR) signaling, where it phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and zeta chains upon antigen recognition [1, 6]. This process is critical for T-cell development in the thymus, as well as the activation and proliferation of mature T cells in response to pathogens [1, 5]. Lck also interacts with co-receptors CD4 and CD8, facilitating their association with the TCR complex [1, 9]. In human pathology, Lck acts as a proto-oncogene; its overexpression or hyperactivation is linked to various cancers, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), and solid tumors such as colorectal and breast cancer [2, 3, 5]. Conversely, biallelic mutations in the LCK gene lead to severe combined immunodeficiency (IMD22), characterized by a lack of functional T cells [9]. Lck is a key therapeutic target for small-molecule inhibitors like dasatinib and saracatinib, which block its ATP-binding site to treat leukemias or manage autoimmune and inflammatory conditions like rheumatoid arthritis and asthma [5, 6, 8]. However, therapeutic use requires careful management of potential immunosuppression and off-target effects due to the structural similarity of Lck to other Src family kinases [6, 11].

Other names

Proto-oncogene c-LckLymphocyte-specific protein tyrosine kinasep56lckLSKLeukocyte C-terminal Src kinaseProtein YT16T cell-specific protein-tyrosine kinasep56-LCK

Inhibition of the tyrosine kinase catalytic activity by binding to the ATP-binding site, preventing the phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) and downstream signaling substrates.