Alt. symbols: IMD22 | LSK | YT16 | p56lck | pp58lck

Approved name: LCK proto-oncogene, Src family tyrosine kinase
Alt. names: lymphocyte-specific protein tyrosine kinase

Location: 1p35.2: 32251244 - 32286165 (+)
Gene type: protein_coding, 14 transcripts.

Scores: LoFtool: 0.128000 | pLI: 0.99942504 | LOEUF: 0.212

HGNC: 6524

NCBI: 3932, RefSeq: NG_023387.1

Ensembl: ENSG00000182866.18

LRG_153 | Status: public

OMIM: 153390

Expression | ProteinAtlas

LCK encodes a Src family non-receptor tyrosine-protein kinase (NRTK) that plays TCR-linked signal transduction pathways and thus an essential role in T cell development and mature function. LCK is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR. LCK contains N-terminal sites for myristylation and palmitylation, a PTK domain, and SH2 and SH3 domains involved in mediating protein-protein interactions with pTyr-containing and Pro-rich motifs, respectively. LCK localizes to the plasma membrane and pericentrosomal vesicles, and binds to cell surface receptors and other signaling molecules, including a constitutive association with the cytoplasmic portions of CD4 and CD8. Upon TCR binding by a peptide antigen-MHC complex, LCK is recruited to the vicinity of the TCR/CD3 complex and phosphorylates ITAM Tyr residues on the C-terminal tails of the TCR-gamma chains and CD3 subunits, initiating TCR/CD3 signaling. Another NRTK ZAP70 is then recruited, phosphorylated and activated by LCK. LCK also interacts with and/or phosphorylates many other substrates, including RUNX3, PTK2B/PYK2, MAPT, RHOH or TYROBP. LCK plays a role in the IL2 receptor-linked signaling pathway that controls T-cell proliferative responses and its own activity is enhanced by IL-2 binding to its receptor. Multiple alternatively spliced variants encoding different isoforms have been described.

Biallelic LOF variants in LCK have been associated with Immunodeficiency 22 [MIM:615758] - see entry for details. Hauck et al. (2012) identified a homozygous missense mutation (c.1022T>C) arising from UPD and leading to pediatric T-cell immunodeficiency (PMID: 22985903). Li et al. (2016) reported a homozygous splice site mutation (c.188-2A>G) in a family affected by atypical epidermodysplasia verruciformis with T-cell defects, HPV infection and virus-induced malignancy (PMID: 27087313). This les ion led to Exon 3 deletion in a T cell-specific isoform, which further led to frameshift mutation and subsequent mRNA decay. Lanz et al. (2023) reported a second case of complete LCK deficiency due to a novel homozygous missense mutation (c.1393T>C, p.C465R) in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immunodeficiency (PMID: 38100037). This led to absent LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Keller et al. (2023) identified 2 patients with CID due to a novel homozygous nonsense mutation that led to reduced expression of a truncated LCK protein lacking parts of the kinase domain and regulatory Tyr residues (PMID: 38112969). Both patients showed progressive loss of naïve T-cell subsets, oligoclonal T cells but detectable differentiation of Tregs, cTfh, and T1/2/17 cells, suggesting residual TCR signal transduction. Lui et al. (2024) identified a homozygous hypomorphic LCK variant (c.1318C>T, p.P440S) in 2 siblings with T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea (PMID: 37962568). More recently, Fusaro et al. (2024) identified a heterozygous in-frame deletion in LCK (F498del) leading to a GOF effect in 2 clinically asymptomatic siblings with T cell abnormalities. See specific entry for details. [Publication pending, presented at ESID 2024] [Load More]