Immune disorders

Immunodeficiency 22

In animal studies, mice lacking Lck display a phenotype resembling severe-combined immunodeficiency (SCID). In additional, transgenic mice that express a dominant-negative form of Lck display severe defects in T-cell development. Furthermore, it was demonstrated in mice that naive, but not memory, CD8+ T-cells require an active Lck for cell activation, possibly explaining the observation that memory T-cells show hyperreactivity to antigens and accerlated immune regulation during a secondary infection. A significantly reduced Lck protein level was observed in an infant with IMD22 and selective CD4 lymphopenia. The reduced expression of Lck was attributed to an alternatively spliced Lck mRNA transcript that lacked exon-7, as no mutation was observed in the Lck coding region. Additionally, the same splice variant was found in a Japanese patient with a similar immunodeficient phenotype and Lck levels ~40% lower than controls. In another case of IMD22, a missense mutation (L341P) was observed at a highly conserved residue in the kinase domain of the Lck protein that resulted in significantly decreased Lck protein expression. In addition, the L341P mutant Lck protein had no kinase catalytic activity and failed to complement TCR signalling in Lck-deficient cells. The patient with the L341P mutation displayed CD4+ T-cell lymphopenia and reduced expression of both T-cell specific CD4 and CD8. In addition, residual T-cells displayed a significant defect in TCR signalling, consistent with the IMD22 phenotype and a loss-of-function of the Lck protein. Furthermore, the binding of the HIV-1 virus to CD4 receptors stimualtes the Lck-Raf-1 pathway, which is thought to be a critical step in the transcriptional activation of the integral HIV-1 provirus and thus the pathogenicity of the disease.
 

LCK may be an oncoprotein (OP) based on its similarity to other Src family protein-tyrosine kinases.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Classical Hodgkin lymphomas (%CFC= +207, p<0.002); Colorectal adenocarcinomas (early onset) (%CFC= +126, p<0.012); Large B-cell lymphomas (%CFC= +543, p<0.042); Oral squamous cell carcinomas (OSCC) (%CFC= +220, p<0.003); Skin melanomas (%CFC= +196, p<0.038); and Vulvar intraepithelial neoplasia (%CFC= +61, p<0.069). The COSMIC website notes an up-regulated expression score for LCK in diverse human cancers of 275, which is 0.6-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 2 for this protein kinase in human cancers was 97% lower than the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.1 % in 25716 diverse cancer specimens. This rate is only 32 % higher than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.78 % in 805 skin cancers tested; 0.56 % in 1152 large intestine cancers tested; 0.17 % in 1941 lung cancers tested.

None > 5 in 20,954 cancer specimens

No deletions, insertions or complex mutations are noted on the COSMIC website.