Staurosporine both activates and inhibits serine/threonine kinases in human platelets.
Ontology highlight
ABSTRACT:
SUBMITTER: Kocher M
PROVIDER: S-EPMC1150052 | biostudies-other | 1991 Apr
REPOSITORIES: biostudies-other
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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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Project description:Distinct membrane receptors activate platelets by Src-family-kinase (SFK)-, immunoreceptor-tyrosine-based-activation-motif (ITAM)-dependent stimulation of spleen tyrosine kinase (Syk). Recently, we reported that platelet activation via glycoprotein (GP) VI or GPIbα stimulated the well-established Syk tyrosine (Y)-phosphorylation, but also stoichiometric, transient protein kinase C (PKC)-mediated Syk serine(S)297 phosphorylation in the regulatory interdomain-B, suggesting possible feedback inhibition. The transient nature of Syk S297 phosphorylation indicated the presence of an unknown Syk pS297 protein phosphatase. In this study, we hypothesize that the S-protein phosphatase 2A (PP2A) is responsible for Syk pS297 dephosphorylation, thereby affecting Syk Y-phosphorylation and activity in human washed platelets. Using immunoblotting, we show that specific inhibition of PP2A by okadaic acid (OA) alone leads to stoichiometric Syk S297 phosphorylation, as analyzed by Zn2+-Phos-tag gels, without affecting Syk Y-phosphorylation. Pharmacological inhibition of Syk by PRT060318 or PKC by GF109203X only minimally reduced OA-induced Syk S297 phosphorylation. PP2A inhibition by OA preceding GPVI-mediated platelet activation induced by convulxin extended Syk S297 phosphorylation but inhibited Syk Y-phosphorylation. Our data demonstrate a novel biochemical and functional link between the S-protein phosphatase PP2A and the Y-protein kinase Syk in human platelets, and suggest that PP2A represents a potential enhancer of GPVI-mediated Syk activity caused by Syk pS297 dephosphorylation.
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Project description:Genomic studies have revealed the presence of Ser/Thr kinases and phosphatases in many bacterial species, although their physiological roles have largely been unclear. Here we review bacterial Ser/Thr kinases (eSTKs) that show homology in their catalytic domains to eukaryotic Ser/Thr kinases and their partner phosphatases (eSTPs) that are homologous to eukaryotic phosphatases. We first discuss insights into the enzymatic mechanism of eSTK activation derived from structural studies on both the ligand-binding and catalytic domains. We then turn our attention to the identified substrates of eSTKs and eSTPs for a number of species and to the implications of these findings for understanding their physiological roles in these organisms.
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Project description:Microcystin-LR (MCLR) exposure has been associated with development of hepatocellular carcinoma (HCC). Many of the carcinogenic mechanisms for MCLR have been attributed to the induction of cell survival and proliferation through altered protein phosphorylation pathways by inhibition of protein phosphatases 1 (PP1) and PP2A. The current study determined MCLR effects on the phosphoproteome in human HepaRG cells. Differentiated HepaRG cells were treated with either vehicle or MCLR followed by phosphoproteomic analysis and Western blotting of MAPK-activated proteins. MCLR decreased cell viability at 24 h at doses as low as 0.03 µM. MCLR also caused a dose-dependent increase in phosphorylation of signaling and stress kinases. The number of decreased phosphosites by 0.1 µM MCLR was similar between the 2 h (212) and 24 h (154) timepoints. In contrast, a greater number of phosphosites were increased at 24 h (567) versus the 2 h timepoint (136), indicating the hyperphosphorylation state caused by MCLR-mediated inhibition of PPs is time-dependent. A kinase perturbation analysis predicted that MCLR exposure at both 2 h and 24 h increased the function of aurora kinase B (AURKB), checkpoint kinase 1 (CHEK1), and serum and glucocorticoid-regulated kinase 1 (SGK1). STRING database analysis of the phosphosites altered by MCLR exposure revealed pathways associated with cell proliferation and survival, including ribosomal protein S6 kinase (RSK), and vascular endothelial growth factor receptor (VEGFR2)-mediated vascular permeability. In addition, several cancer-related KEGG pathways were enriched at both 2 h and 24 h timepoints, and multiple cancer-related disease-gene associations were identified at the 24 h timepoint. Many of the kinases and pathways described above play crucial roles in the development of HCC by affecting processes such as invasion and metastasis. Overall, our data indicate that MCLR-mediated changes in protein phosphorylation involve biological pathways related to carcinogenesis that may contribute to the development of HCC.
2025-02-05 | PXD054405 | Pride
Project description:The molecular mechanisms regulating the spectacular cytodifferentiation observed during spermiogenesis are poorly understood. We have recently identified a murine testis-specific serine kinase (tssk) 1, constituting a novel subfamily of serine/threonine kinases. Using low stringency screening we have isolated and molecularly characterized a second closely related family member, tssk 2, which is probably the orthologue of the human DGS-G gene. Expression of tssk 1 and tssk 2 was limited to the testis of sexually mature males. Immunohistochemical staining localized both kinases to the cytoplasm of late spermatids and to structures resembling residual bodies. tssk 1 and tssk 2 were absent in released sperms in the lumen of the seminiferous tubules and the epididymis, demonstrating a tight window of expression restricted to the last stages of spermatid maturation. In vitro kinase assays of immunoprecipitates containing either tssk 1 or tssk 2 revealed no autophosphorylation of the kinases, however, they led to serine phosphorylation of a coprecipitating protein of approximately 65 kD. A search for interacting proteins using the yeast two-hybrid system with tssk 1 and tssk 2 cDNA as baits and a prey cDNA library from mouse testis, led to the isolation of a novel cDNA, interacting specifically with both tssk 1 and tssk 2, and encoding the coprecipitated 65-kD protein phosphorylated by both kinases. Interestingly, expression of the interacting clone was also testis specific and paralleled the developmental expression observed for the kinases themselves. These results represent the first demonstration of the involvement of a distinct kinase family, the tssk serine/threonine kinases, together with a substrate in the cytodifferentiation of late spermatids to sperms.
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Project description:Microtubule-Associated Serine/Threonine (MAST) kinases represent an evolutionary conserved branch of the AGC protein kinase superfamily in the kinome. Since the discovery of the founding member, MAST2, in 1993, three additional family members have been identified in mammals and found to be broadly expressed across various tissues, including the brain, heart, lung, liver, intestine and kidney. The study of MAST kinases is highly relevant for unraveling the molecular basis of a wide range of different human diseases, including breast and liver cancer, myeloma, inflammatory bowel disease, cystic fibrosis and various neuronal disorders. Despite several reports on potential substrates and binding partners of MAST kinases, the molecular mechanisms that would explain their involvement in human diseases remain rather obscure. This review will summarize data on the structure, biochemistry and cell and molecular biology of MAST kinases in the context of biomedical research as well as organismal model systems in order to provide a current profile of this field.
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Project description:The signal transduction pathway of prokaryotes involves a peptidoglycan synthesis cluster (PG) to sense external stimuli. One of the major components of the PG synthesis cluster is protein kinases (pknA - G). The sequence data of probiotic eSTKs (Eukaryotic like Serine, Threonine kinases) are obscure, scarce and essentially required to understand the role of probiotic microbes in combating infectious diseases. The most essential need to understand and develop certain therapeutic drugs against pathogens is the eSTK sequence data. Hence, we developed a comprehensive user-friendly data repository of probiotic eSTK's (PeSTK), which holds 830 STK sequences. Therefore, the data resource of PeSTK developed is unique, an open-access very summative containing various probiotic eSTK's in a single locality. The sequence datasets of the eSTK developed with easy-to-operate browsing as well as searching. Therefore, eSTK data resources should be useful for sequence-based studies and drug development. The sequence datasets are available at Figshare Digital Object Identifier/DOI of the sequences is https://doi.org/10.6084/m9.figshare.146606 .
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Project description:BackgroundHIV-1 protease (PR) is essential for viral infectivity as it cleaves Gag and Gag-Pol polyprotein precursors during viral maturation. Recent evidence suggests that cellular proteins can also be cleaved by PR, perhaps representing an important viral strategy to counter host defense mechanisms. Receptor-interacting protein kinase 1 (RIPK1) and RIPK2 belong to a family of serine/threonine kinases with conserved domain architecture and important functions in apoptosis, necrosis and innate immunity.ResultsWe found that RIPK1 and RIPK2 but not other members of the RIP kinase family are cleaved by HIV-1 PR. In RIPK1, we identified a putative PR cleavage site; a mutation at this site rendered RIPK1 resistant to PR cleavage. RIPK1 and RIPK2 were cleaved during HIV-1 infection of T cell lines or primary activated CD4(+) T cells. Interfering with the viral life cycle at different stages by the addition of specific inhibitors against RT, integrase, or PR, completely prevented RIPK1 and RIPK2 cleavage. Cleavage of RIPK1 disrupted RIPK1/RIPK3 complex formation and RIPK1-mediated induction of NF-kB.ConclusionsThese findings indicate that RIPK1 and RIPK2 are targets of HIV-1 PR activity during infection, and their inactivation may contribute to modulation of cell death and host defense pathways by HIV-1.
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