Deciphering the Receptor-Mediated Signaling Pathways of Interleukin-19 and Interleukin-20.

Interleukin-19 (IL-19) and Interleukin-20 (IL-20) are inflammatory cytokines belonging to the IL-10 family with immunoregulatory properties. Emerging evidence highlights the importance of association of these cytokines with both immunological and inflammatory disorders, including chronic inflammation, cardiac dysfunction, and cancer. IL-19 and IL-20 bind to the heterodimeric receptor complex and induce multiple downstream signaling cascades by activating the signal transducer and activator of transcription 3 (STAT3), Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), AKT serine/threonine kinase 1 (AKT1), and NFKB inhibitor alpha (NFKBIA), leading to proinflammatory and anti-inflammatory reactions in cancer, inflammation, tumor microenvironment, and infectious diseases. Considering the significant role of these cytokines, we integrated its cellular signaling network by combining multiomics molecular events associated with 56 molecules of induced by IL-19 and 156 molecules of by IL-20. The reactions of these signaling events are classified into enzyme catalysis/post-translational modifications, activation/inhibition events, molecular associations, gene regulations at the mRNA and protein level, and the protein translocation events. We believe that this signaling pathway map would serve as a knowledge base, that aid researchers and clinicians to understand and explore the intricate mechanisms and identify novel signaling components and therapeutic targets for diseases associated with dysregulated IL-19 and IL-20 signaling.

A global phosphosite-correlated network map of Thousand And One Kinase 1 (TAOK1).

Thousand and one amino acid kinase 1 (TAOK1) is a sterile 20 family Serine/Threonine kinase linked to microtubule dynamics, checkpoint signaling, DNA damage response, and neurological functions. Molecular-level alterations of TAOK1 have been associated with neurodevelopment disorders and cancers. Despite their known involvement in physiological and pathophysiological processes, and as a core member of the hippo signaling pathway, the phosphoregulatory network of TAOK1 has not been visualized. Aimed to explore this network, we first analyzed the predominantly detected and differentially regulated TAOK1 phosphosites in global phosphoproteome datasets across diverse experimental conditions. Based on 709 qualitative and 210 quantitative differential cellular phosphoproteome datasets that were systematically assembled, we identified that phosphorylation at Ser421, Ser9, Ser965, and Ser445 predominantly represented TAOK1 in almost 75% of these datasets. Surprisingly, the functional role of all these phosphosites in TAOK1 remains unexplored. Hence, we employed a robust strategy to extract the phosphosites in proteins that significantly correlated in expression with predominant TAOK1 phosphosites. This led to the first categorization of the phosphosites including those in the currently known and predicted interactors, kinases, and substrates, that positively/negatively correlated with the expression status of each predominant TAOK1 phosphosites. Subsequently, we also analyzed the phosphosites in core proteins of the hippo signaling pathway. Based on the TAOK1 phosphoregulatory network analysis, we inferred the potential role of the predominant TAOK1 phosphosites. Especially, we propose pSer9 as an autophosphorylation and TAOK1 kinase activity-associated phosphosite and pS421, the most frequently detected phosphosite in TAOK1, as a significant regulatory phosphosite involved in the maintenance of genome integrity. Considering that the impact of all phosphosites that predominantly represent each kinase is essential for the efficient interpretation of global phosphoproteome datasets, we believe that the approach undertaken in this study is suitable to be extended to other kinases for accelerated research.

Tyr352 as a Predominant Phosphosite in the Understudied Kinase and Molecular Target, HIPK1: Implications for Cancer Therapy.

Homeodomain-interacting protein kinase 1 (HIPK1) is majorly found in the nucleoplasm. HIPK1 is associated with cell proliferation, tumor necrosis factor-mediated cellular apoptosis, transcription regulation, and DNA damage response, and thought to play significant roles in health and common diseases such as cancer. Despite this, HIPK1 remains an understudied molecular target. In the present study, based on a systematic screening and mapping approach, we assembled 424 qualitative and 44 quantitative phosphoproteome datasets with 15 phosphosites in HIPK1 reported across multiple studies. These HIPK1 phosphosites were not currently attributed to any functions. Among them, Tyr352 within the kinase domain was identified as the predominant phosphosite modulated in 22 differential datasets. To analyze the functional association of HIPK1 Tyr352, we first employed a stringent criterion to derive its positively and negatively correlated protein phosphosites. Subsequently, we categorized the correlated phosphosites in known interactors, known/predicted kinases, and substrates of HIPK1, for their prioritized validation. Bioinformatics analysis identified their significant association with biological processes such as the regulation of RNA splicing, DNA-templated transcription, and cellular metabolic processes. HIPK1 Tyr352 was also identified to be upregulated in Her2+ cell lines and a subset of pancreatic and cholangiocarcinoma tissues. These data and the systems biology approach undertaken in the present study serve as a platform to explore the functional role of other phosphosites in HIPK1, and by extension, inform cancer drug discovery and oncotherapy innovation. In all, this study highlights the comprehensive phosphosite map of HIPK1 kinase and the first of its kind phosphosite-centric analysis of HIPK1 kinase based on global-level phosphoproteomics datasets derived from human cellular differential experiments across distinct experimental conditions.

Cisplatin and Procaterol Combination in Gastric Cancer? Targeting Checkpoint Kinase 1 for Cancer Drug Discovery and Repurposing by an Integrated Computational and Experimental Approach.

Checkpoint kinase 1 (CHK1), a serine/threonine kinase, plays a crucial role in cell cycle arrest and is a promising therapeutic target for drug development against cancers. CHK1 coordinates cell cycle checkpoints in response to DNA damage, facilitating repair of single-strand breaks, and maintains the genome integrity in response to replication stress. In this study, we employed an integrated computational and experimental approach to drug discovery and repurposing, aiming to identify a potent CHK1 inhibitor among existing drugs. An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. This model, characterized by seven key molecular features, guided the screening of a library of drugs through molecular docking. The top 10% of scored ligands were further examined, with procaterol emerging as the leading candidate. Procaterol demonstrated interaction patterns with the CHK1 active site similar to CHK1 inhibitor (CCT245737), as shown by molecular dynamics analysis. Subsequent in vitro assays, including cell proliferation, colony formation, and cell cycle analysis, were conducted on gastric adenocarcinoma cells treated with procaterol, both as a monotherapy and in combination with cisplatin. Procaterol, in synergy with cisplatin, significantly inhibited cell growth, suggesting a potentiated therapeutic effect. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer.

A network map of macrophage-stimulating protein (MSP) signaling.

Macrophage-stimulating protein (MSP), a serum-derived growth factor belonging to the plasminogen-related kringle domain family, is mainly produced by the liver and released into the blood. MSP is the only known ligand for RON ("Recepteur d'Origine Nantais", also known as MST1R), which is a member of the receptor tyrosine kinase (RTK) family. MSP is associated with many pathological conditions, including cancer, inflammation, and fibrosis. Activation of the MSP/RON system regulates main downstream signaling pathways, including phosphatidylinositol 3-kinase/ AKT serine/threonine kinase/ (PI3-K/AKT), mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK) & Focal adhesion kinase (FAK). These pathways are mainly involved in cell proliferation, survival, migration, invasion, angiogenesis & chemoresistance. In this work, we created a pathway resource of signaling events mediated by MSP/RON considering its contribution to diseases. We provide an integrated pathway reaction map of MSP/RON that is composed of 113 proteins and 26 reactions based on the curation of data from the published literature. The consolidated pathway map of MSP/RON mediated signaling events contains seven molecular associations, 44 enzyme catalysis, 24 activation/inhibition, six translocation events, 38 gene regulation events, and forty-two protein expression events. The MSP/RON signaling pathway map can be freely accessible through the WikiPathways Database URL: https://classic.wikipathways.org/index.php/Pathway:WP5353 .