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Basics of Allergy
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Rafeul Alam, Dipa K Sheth, Magdalena M Gorska
Two tyrosine kinases—Lck (Lymphocyte-specific protein tyrosine kinase) and ZAP70 (zeta-associated protein 70) play a critical role in the selection of CD4 and CD8 T cells, respectively. Patients with congenital deficiency of Lck have severe combined immunodeficiency because of the failure of CD4 differentiation; ZAP70 deficiency results in a severe defect of CD8 T cell differentiation. A small fraction of T cells, mostly of gd subtype, is negative for both CD4 and CD8 (double negative) (Carding et al. 2002).
T Cells:Regulation and Cellular Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
The cytoplasmic domains of both CD4 and CD8 are associated with the protein tyrosine kinase lck, a member of the src family of tyrosine kinases. Cross-linking of either CD4 or CD8 with antibodies activates lck which may then phosphorylate components of the TCRCD3 complex. The association of lck with CD4 and CD8 is different, but both molecules are important co-stimulators in the TCR-CD3-antigen-MHC interaction.
Cell-mediated immunity
Published in Gabriel Virella, Medical Immunology, 2019
José C. Crispín, Gabriel Virella
TCR-initiated signaling can be divided into three distinct phases: proximal, linker/adapter, and distal (Figure 11.2). TCR engagement triggers the proximal phase, which consists on the phosphorylation of the ITAMs of the CD3 complex by the src-related tyrosine kinase Lck, which is noncovalently associated with the cytoplasmic domains of CD4 and of CD8. The cell surface molecule CD45, expressed by all leukocytes, contains an intracytoplasmic phosphatase that in T cells regulates the activity of src family kinases, including Lck. Phosphorylation of the ITAMs located in the CD3ζ subunit allows the coupling of a third tyrosine kinase, called ZAP-70 (for ζ-associated protein of 70 KDa). When ZAP-70 associates with the CD3 complex, Lck stabilizes its activity by phosphorylating it in a key residue.
LCK, FOXC1 and hsa-miR-146a-5p as potential immune effector molecules associated with rheumatoid arthritis
Published in Biomarkers, 2023
Xuemeng Chen, Li Xie, Yi Jiang, Ronghua Zhang, Wei Wu
Genes causing complex diseases always participate in common biological processes in various kinds of biological networks (Zhang et al. 2020). Co-expression networks could provide information of co-regulation genes that function in the regulation processes and relationships of transcriptome components disturbed, and enrichment analysis of DEGs is necessary (Kotni et al. 2016, Kliebenstein 2020). We constructed a PPI network encoded by DEGs and identified the subsequent top 10 closely related genes: LCK, GZMA, GZMB, CD2, LAG3, IL-15, TNFRSF4, CD247, CCR5 and CCR7. These genes are key nodes for the construction a PPI network and play a distinct role in the pathogenesis of RA. Lymphocyte-specific protein tyrosine kinase (LCK), an Src family member, is a lymphoid-specific cytosolic protein tyrosine kinase that is essential for activating T cell receptor signalling and T cells (Isakov and Biesinger 2000).
Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1
Published in Expert Opinion on Investigational Drugs, 2022
Hue Tu Quach, Zhaohua Hou, Rebecca Y. Bellis, Jasmeen K. Saini, Alfredo Amador-Molina, Prasad S. Adusumilli, Yuquan Xiong
Programmed cell death 1 (PD-1; also known as CD279) [7] – expressed during T-cell activation and maturation – plays a substantial role in maintaining peripheral tolerance [8] and countering active signals [9] through TCR and CD28. PD-1 ligates to programmed cell death 1 ligand 1 (PD-L1; also known as CD274 and B7‑H1) and programmed cell death 1 ligand 2 (PD-L2; also known as CD273 and B7‑DC) [10]. This ligation results in signaling pathways downstream of PD-1 contributing to the regulation of T-cell function and differentiation and the fine-tuning of T-cell fate [11]. In the proximal signaling, PD-1 was found to inhibit the phosphorylation of lymphocyte-specific protein tyrosine kinase (Lck)/zeta-chain-associated protein kinase 70 (ZAP70) and protein kinase C-theta (PKCθ) [12], and act as the linker for activation of T cells (LAT) docking on the T-cell membrane. PD-1 regulates the distal signaling by suppressing phosphorylation of Akt, Erk, and Ras [13] in a SHP1/2-dependent manner [14], resulting in not only the attenuation of cytotoxic cytokines transcription and cell cycle but also reprogramming of T-cell metabolism [15] and consequently cell exhaustion and apoptosis survival.
New horizons in drug discovery of lymphocyte-specific protein tyrosine kinase (Lck) inhibitors: a decade review (2011–2021) focussing on structure–activity relationship (SAR) and docking insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Ahmed Elkamhawy, Eslam M. H. Ali, Kyeong Lee
Lymphocyte-specific protein tyrosine kinase (Lck), a 56 KDa protein, is a member of the Src family of non-receptor protein kinases. Lck is involved in the phosphorylation process of a number of intracellular signalling molecules such as IL-2-inducible T-cell kinase (ITK), protein kinase C, Phosphoinositide 3-kinase (PI3K), and Zeta-chain-associated protein kinase 70 (ZAP-70). Accordingly, it regulates numerous cellular processes including cell cycle control, cell adhesion, motility, proliferation, and differentiation. The function of Lck has been extensively studied and various reports revealed different mechanistic insights into the regulation of its activity including its major role as a key activator of T cells via T cell antigen receptors (TCR) signalling1–5. In addition to T cells, Lck is expressed in natural killer (NK) cells, NK T cells, CD5+ B-1 B cells, germinal centre and to a lesser extent in mantle zone B cells, aryl hydrocarbon receptor-activated primary human B cells, and brain including the hippocampus, cerebellum and retina6–10. In addition to leukaemia, Lck expression was also detected in a number of solid cancers including colon cancer, lung carcinoma, and breast cancer11–16, which led to the hypothesis that Lck may also have cancer promoting functions and hence may act as a potential therapeutic target for solid cancers.