LCK

Lck, short for lymphocyte-specific protein tyrosine kinase, is a member of the Src family of non-receptor protein tyrosine kinases. The LCK gene encodes this 56–60 kDa cytoplasmic kinase, which is expressed predominantly in T lymphocytes and thymocytes. Lck is anchored to the inner plasma membrane by N-terminal lipidation (myristoylation and palmitoylation) and contains SH3, SH2, and kinase domains, enabling it to participate in early T cell receptor signaling.

Upon T cell receptor (TCR) engagement, Lck is recruited to the receptor complex via interactions with CD4 or CD8 co-receptors and is regulated by phosphorylation. Activation involves dephosphorylation of the C-terminal tyrosine (Tyr505) by phosphatases such as CD45 and subsequent phosphorylation of the activation loop tyrosine (Tyr394). Active Lck phosphorylates immunoreceptor tyrosine activation motifs (ITAMs) on CD3 and the zeta chain, creating docking sites for ZAP-70. Activated ZAP-70 phosphorylates downstream adaptors like LAT and SLP-76, propagating signals that activate PLC-γ1, elevate intracellular calcium, and trigger NFAT, NF-κB, and AP-1 transcriptional programs, driving T cell activation, proliferation, and differentiation.

Biological significance includes a critical role in T cell development in the thymus; Lck deficiency impairs T cell development and signaling. Clinically, altered Lck activity has been linked to immunodeficiency disorders and to autoimmune disease and cancer in which T cell signaling is perturbed. Lck is a target of small-molecule inhibitors used in cancer therapy (for example, dasatinib), reflecting its broader relevance in cell signaling.