Exploration of the therapeutic aspects of Lck: A kinase target in inflammatory mediated pathological conditions

Singh, Pankaj Kumar; Kashyap, Aanchal; Silakari, Om

doi:10.1016/j.biopha.2018.10.002

Cited by 59 publications

(27 citation statements)

References 64 publications

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“…CD45 deficiency results in T-and B-lymphocyte dysfunction in the form of severe combined immune deficiency (Courtney, Lo & Weiss, 2018;Chakraborty & Weiss, 2014). Lck is a member of the Src family of nonreceptor protein tyrosine kinases that phosphorylate ZAP70 and ITK (Rohrs, Wang & Finley, 2016;Singh, Kashyap & Silakari, 2018). Zeta-chain associated protein kinase (ZAP70), a member of the Syk family kinase, is predominantly a tyrosine kinase protein that is involved in T cell receptor (TCR) signalling initiation and subsequent T cell activation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages

Wang

Chao

et al. 2020

PeerJ

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Background The submandibular glands, as major salivary glands, participate in rumen digestion in goats. Sialic acid, lysozyme, immunoglobulin A (IgA), lactoferrin and other biologically active substances secreted in the submandibular glands were reported in succession, which suggests that the submandibular gland may have immune functions in addition to participating in digestion. The aim of this study was to map the expression profile of differentially expressed genes (DEGs) at three different stages by transcriptome sequencing, screen immune-related genes and pathways by bioinformatics methods, and predict the immune function of submandibular glands at different developmental stages. Methods Nine submandibular gland tissue samples were collected from groups of 1-month-old kids, 12-month-old adolescent goats and 24-month-old adult goats (3 samples from each group), and high-throughput transcriptome sequencing was conducted on these samples. The DEGs among the three stages were screened and analysed. Key genes and signalling pathways were selected via protein-protein interaction (PPI) network analysis. Results The results revealed 2,706, 2,525 and 52 DEGs between 1-month-old and 12-month-old goats, between 1-month-old and 24-month-old goats, and between 12-month-old and 24-month-old goats, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that most of the DEGs were enriched in immune- related GO terms and pathways. Based on functional enrichment analysis and network analysis, 10 genes (PTPRC, CD28, SELL, LCP2, MYC, LCK, ZAP70, ITGB2, SYK and CCR7), two signalling pathways (the T cell receptor signalling pathway and the NF-κβ signalling pathway) and eight GO terms (T cell receptor signalling pathway, neutrophil mediated immunity, B cell mediated immunity, regulation of alpha-beta T cell activation, positive regulation of T cell proliferation, regulation of leukocyte differentiation, positive regulation of antigen receptor-mediated signalling pathway, positive regulation of lymphocyte proliferation) that may play key roles in the immune functions of the goat submandibular glands at different developmental stages were identified. Moreover, we found that eight antibacterial peptide-encoding genes were downregulated in the tuberculosis and salivary secretion pathways, while all immunoglobulins were upregulated in 10 immune system pathways. These findings indicate that the submandibular glands may be important immunological organs during the growth process of goats and that the immune function of these glands gradually weakens with age up to 12 months but remains relatively stable after 12 months of age. Overall, this study will improve our understanding of transcriptional regulation related to goat submandibular gland immune function.

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Section: Discussionmentioning

confidence: 99%

Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages

Wang

Chao

et al. 2020

PeerJ

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“…4 A, Additional file 7 : Table S6). Imatinib mesylate (brand name: Gleevec) targets several Src family tyrosine kinases, including LCK, which is involved in T cell development and has a recognized role in inflammation [ 80 ]. Bacterial proteins targeting these same kinases are consistently enriched in healthy controls across both IBD and three CRC cohorts we analyzed (Fig.…”

Section: Discussionmentioning

confidence: 99%

Host-microbiome protein-protein interactions capture disease-relevant pathways

2022

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Background Host-microbe interactions are crucial for normal physiological and immune system development and are implicated in a variety of diseases, including inflammatory bowel disease (IBD), colorectal cancer (CRC), obesity, and type 2 diabetes (T2D). Despite large-scale case-control studies aimed at identifying microbial taxa or genes involved in pathogeneses, the mechanisms linking them to disease have thus far remained elusive. Results To identify potential pathways through which human-associated bacteria impact host health, we leverage publicly-available interspecies protein-protein interaction (PPI) data to find clusters of microbiome-derived proteins with high sequence identity to known human-protein interactors. We observe differential targeting of putative human-interacting bacterial genes in nine independent metagenomic studies, finding evidence that the microbiome broadly targets human proteins involved in immune, oncogenic, apoptotic, and endocrine signaling pathways in relation to IBD, CRC, obesity, and T2D diagnoses. Conclusions This host-centric analysis provides a mechanistic hypothesis-generating platform and extensively adds human functional annotation to commensal bacterial proteins.

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“…zDHHC2 inhibition could be of use for the management of several auto-immune disorders involving the lymphocyte-specific protein tyrosine kinase lck. S-acylation of this protein, which is essential for T cell activation, is mediated by zDHHC2 (54–56). There may also be potential for employing selective inhibitors of zDHHC enzymes for the treatment of some infectious diseases.…”

Section: Discussionmentioning

confidence: 99%

Development of a novel high-throughput screen for the identification of new inhibitors of protein S-acylation

Salaün

Takizawa

Galindo

et al. 2022

Preprint

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Protein S-acylation is a reversible post-translational modification that modulates the localisation and function of many cellular proteins. S-acylation is mediated by a family of zinc finger DHHC domain-containing proteins encoded by 23 distinct ZDHHC genes in the human genome. These enzymes catalyse S-acylation in a two-step process involving auto-acylation of the cysteine residue in the catalytic DHHC motif followed by transfer of the acyl chain to a substrate cysteine. S-acylation is essential for many fundamental physiological processes, and there is growing interest in zDHHC enzymes as novel drug targets for a range of disorders. However, there is currently a lack of chemical modulators of S-acylation either for use as tool compounds or for potential development for therapeutic purposes. In this study, we developed and implemented a novel FRET-based high throughput assay for the discovery of compounds that interfere with auto-acylation of zDHHC2, an enzyme that is implicated in neuronal S-acylation pathways. A screen of >350,000 compounds identified two related tetrazole containing compounds (TTZ-1 and -2) that inhibited both zDHHC2 auto-acylation and substrate S-acylation in cell-free systems. Furthermore, these compounds were also active in HEK293T cells, where they inhibited substrate S-acylation mediated by different zDHHC enzymes, with some apparent isoform selectivity. Resynthesis of the hit compounds confirmed their activity, providing sufficient quantities of material for further investigations. The assays developed herein provide novel strategies to screen for zDHHC inhibitors, and the identified compounds add to the chemical toolbox for interrogating the cellular activities of S-acylation and zDHHC enzymes.

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Exploration of the therapeutic aspects of Lck: A kinase target in inflammatory mediated pathological conditions

Cited by 59 publications

References 64 publications

Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages

Transcriptome analysis reveals potential immune function-related regulatory genes/pathways of female Lubo goat submandibular glands at different developmental stages

Host-microbiome protein-protein interactions capture disease-relevant pathways

Development of a novel high-throughput screen for the identification of new inhibitors of protein S-acylation

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