Serine threonine kinase 24 (STK24) mediates immune evasion signals in tumors by regulating immuno-suppressive molecules
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199632 | GEO | 2023/07/01
REPOSITORIES: GEO
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Project description:Serine threonine kinase 24 (STK24) mediates immune evasion signals in tumors by regulating immuno-suppressive molecules
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Project description:Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-?B and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-?B activation and expression of chemokines and cytokines in a kinase activity-independent manner. The IL-17-induced inflammatory response was significantly reduced in Stk24-deficient mice. In addition, the severity of experimental autoimmune encephalomyelitis was markedly reduced in mice with a deficiency of Stk24 in non-hematopoietic cells. We further demonstrated that Stk24 directly interacts with TAK1 and IKK? and promotes the formation of TAK1/IKK complexes, leading to enhanced IKK?/NF-?B activation and downstream cytokines and chemokines induction. Collectively, our findings suggest that Stk24 plays an important role in controlling IL-17-triggered inflammation and autoimmune diseases and provides new insight into the therapeutic targets of IL-17-mediated inflammatory disease.
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Project description:STK16 (Ser/Thr kinase 16, also known as Krct/PKL12/MPSK1/TSF-1) is a myristoylated and palmitoylated Ser/Thr protein kinase that is ubiquitously expressed and conserved among all eukaryotes. STK16 is distantly related to the other kinases and belongs to the NAK kinase family that has an atypical activation loop architecture. As a membrane-associated protein that is primarily localized to the Golgi, STK16 has been shown to participate in the TGF-β signaling pathway, TGN protein secretion and sorting, as well as cell cycle and Golgi assembly regulation. This review aims to provide a comprehensive summary of the progress made in recent research about STK16, ranging from its distribution, molecular characterization, post-translational modification (fatty acylation and phosphorylation), interactors (GlcNAcK/DRG1/MAL2/Actin/WDR1), and related functions. As a relatively underexplored kinase, more studies are encouraged to unravel its regulation mechanisms and cellular functions.
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Project description:Gastric cancer patients often present with distant metastasis and advanced stages. Suppressing serine/threonine-protein kinase 24 (STK24, also known as MST3) is known to promote gastric tumorigenesis. Here, we investigated the effects from STK24 on the metastasis of gastric cancer. We used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technology for genetic knockout of STK24 at the genomic DNA level in human MKN45 and mouse M12 gastric cancer cells. To assess the consequences of STK24 knockdown, western blot, cell migration, and wound healing assays were conducted in vitro. An in vivo mouse model of liver metastasis was established and tested, and bioinformatics analyses were performed. The knockdown of the STK24 gene enhanced cell migration and increased liver metastasis in the mouse model of gastric cancer. STK24-silenced tumors suppressed CD4+ T cells and enhanced the expansion of CD11b+Ly6C+ myeloid-derived suppressor cells (MDSCs) and F4/80+ macrophages in the spleen of the mice. In MKN45 cells, STK24 silencing resulted in downregulation of E-cadherin (gene CDH1, Cadherin-1, or epithelial cadherin). In 38 paired specimens of gastric adenocarcinomas and normal tissues, we examined STK24 and CDH1 expression levels via western blot; a positive correlation between the expression levels of STK24 and CDH1 was found (R2 = 0.5507, P = 9.72 × 10-8). Furthermore, in Oncomine database and Kaplan-Meier plotter analysis, the loss of CDH1, increase in CCL2, and upregulation of CD44 were correlated with poor prognosis of gastric cancer patients. Our results demonstrate that knockdown of STK24 increases cell migration through suppressing CDH1 and enhancing CD44. In experimental model of metastatic gastric cancer in syngeneic inbred mice, STK24 is important for immune suppression through expansion of CD11b+Ly6C+ MDSCs and F4/80+ macrophages. We confirmed that STK24 is an inhibitor of gastric cancer metastasis.
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Project description:The Mycobacterium tuberculosis genome encodes 11 serine/threonine protein kinases (STPKs). A similar number of two-component systems are also present, indicating that these two signal transduction mechanisms are both important in the adaptation of this bacterial pathogen to its environment. The M. tuberculosis phosphoproteome includes hundreds of Ser- and Thr-phosphorylated proteins that participate in all aspects of M. tuberculosis biology, supporting a critical role for the STPKs in regulating M. tuberculosis physiology. Nine of the STPKs are receptor type kinases, with an extracytoplasmic sensor domain and an intracellular kinase domain, indicating that these kinases transduce external signals. Two other STPKs are cytoplasmic and have regulatory domains that sense changes within the cell. Structural analysis of some of the STPKs has led to advances in our understanding of the mechanisms by which these STPKs are activated and regulated. Functional analysis has provided insights into the effects of phosphorylation on the activity of several proteins, but for most phosphoproteins the role of phosphorylation in regulating function is unknown. Major future challenges include characterizing the functional effects of phosphorylation for this large number of phosphoproteins, identifying the cognate STPKs for these phosphoproteins, and determining the signals that the STPKs sense. Ultimately, combining these STPK-regulated processes into larger, integrated regulatory networks will provide deeper insight into M. tuberculosis adaptive mechanisms that contribute to tuberculosis pathogenesis. Finally, the STPKs offer attractive targets for inhibitor development that may lead to new therapies for drug-susceptible and drug-resistant tuberculosis.
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