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Downstream Signaling 2
Published in James E. Ferrell, Systems Biology of Cell Signaling, 2021
However, a simpler type of coupling can still take place. There are a number of examples now where the phosphorylation of one residue, even in an intrinsically disordered region, produces a phosphoepitope that can serve as a docking site for a protein kinase—sometimes, but not always, the same kinase that carried out the first priming phosphorylation. In this way, a priming phosphorylation can promote subsequent phosphorylations through enforced proximity, a simple but powerful alternative to allostery. The cyclin–Cdk–Cks complex is one nice example of a kinase that makes use of priming phosphorylations, as shown schematically in Figure 5.11. In this case, the Cks subunit (called Suc1 in S. pombe, Cks1 in S. cerevisiae, and Cks1 or 2 in vertebrates) serves as the phosphoepitope-binding subunit, binding phosphothreonine residues in a particular primary sequence context and facilitating the phosphorylation of other nearby serine and threonine residues. This priming-and-multisite-phosphorylation theme is probably relevant to the regulation of scores of substrate proteins by the cell cycle Cdk complexes. Glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1) are two other kinases that depend on a priming phosphorylation to carry out multisite phosphorylation and regulate their substrates. In these cases, the priming phosphorylation interacts with a region of the kinase’s catalytic domain rather than a separate subunit, but otherwise the basic phenomenon is similar.
Regulatory Mechanism of Axonemal Dynein
Published in Keiko Hirose, Handbook of Dynein, 2019
In Chlamydomonas flagella, inner-arm dynein-f/I1 is regulated by the phosphorylation of IC138. Inhibitor of cAMP-dependent protein kinase (PKA) or casein kinase 1 (CK1) dephosphorylates IC138 and increases the velocity of microtubule sliding [29, 32, 77, 157]. Dephosphorylation of IC138 is thought to be due to PP1 or PP2A. These phosphatases are located in the central pair or outer doublet microtubules, respectively [22, 158]. PKA anchoring protein AKAP is located at the base of the radial spoke (RSP3), so in the vicinity of inner-arm dynein [26]. Thus, the regulation of IC138 in innerarm dynein-I1/f is caused by protein kinases and phosphatases in cooperation with the central pair/radial spoke complex [121]. The same regulatory system appears conserved in sperm flagella, since the Ciona ortholog of IC140, IC116, is dephosphorylated when sperm motility is activated [42].
Production of Life-Saving Drugs from Marine Sources
Published in Prasenjit Mondal, Ajay K. Dalai, Sustainable Utilization of Natural Resources, 2017
Hymenialdisine (191), a sponge-derived brominated pyrrole isolated from marine sponges of the genera Hymeniacidon, Acanthella, Axinella, and Pseudaxinyssa (Nguyen and Tepe 2009), inhibited GSK-3, casein kinase 1 (CK1), and cyclin-dependent kinases (CDK 1 and 5) and consequently suppressed hyperphosphorylation of microtubule-associated protein (MAP)-1B and tau. Compound 191 exerted its effect by interacting with the ATP binding pocket of CDK2 (Meijer et al. 2000). A related compound leucettamine B (192) derived from the Palauan sponge Leucetta microraphis also inhibited cyclin-dependent kinases (Chan et al. 1993; Watanabe et al. 2000). An indole alkaloid, indirubin (193), has also been identified as an inhibitor of GSK-3, CDK5, and P25 that are involved in abnormal tau phosphorylation in Alzheimer’s disease (Leclerc et al. 2001). Palinurin (194), a sponge-derived sesterterpene, inhibited both GSK-3α and GSK-3β, and related compounds ircinin-1 and ircinin-2 inhibited GSK-3β (Bidon-Chanal et al. 2013).
Systems toxicology approach explores target-pathway relationship and adverse health impacts of ubiquitous environmental pollutant bisphenol A
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Manigandan Nagarajan, Gobichettipalayam Balasubramaniam Maadurshni, Jeganathan Manivannan
The kinome wide interaction profile of BPA was predicted by employing the KinomeX tool which implements comprehensive profiling on kinome-wide activity for small molecules, and might can depict overall selectivity and selectivity toward a sub-family of kinases based upon the predicted kinase profile (Li et al. 2019). In particular, kinome wide target screening is considered as more efficient approach toward the discovery of new kinase inhibitors (Miduturu et al. 2011) and characterizing systems-level drug action (Vidović et al., 2014). In the current study, approximately 17 kinases were predicted as possible targets of BPA. Among these, the eIF2α kinase heme-regulated inhibitor (HRI) exhibited the highest interaction score which is known to protect the host from infection by regulating intracellular pathogen trafficking (Bahnan et al. 2018). Subsequently, the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation (Mifflin, Ofengeim, and Yuan 2020) and its inhibitors may possess significant potential for treatment of inflammatory disorders and cancer metastasis (Hou et al. 2019). Further, several investigators suggested that mammalian PAS domain-containing serine/threonine-protein kinase (PASK) is involved in glucose metabolism, insulin secretion and blood glucose levels by its action on pancreatic islet α/β cells and glycogen synthase (GS), in which the PASK knockout mice (PASK-/-) are protected from obesity, liver triglyceride accumulation and insulin resistance (Zhang et al. 2015). Our study, focused on casein kinase 2 alpha 1(CSNK2A1) and casein kinase 2 alpha 2(CSNK2A2,) catalytic subunits of casein kinase II (CSNK2) which is a pleiotropic serine/threonine kinase participates in diverse cellular processes. In this regard, recent evidence suggested that CSNK2A1 plays important oncogenic roles in gastric cancer invasion via epithelial-mesenchymal transition (EMT) and the PI3K-Akt-mTOR signaling pathways (Jiang et al. 2019). In addition, a genome-wide association study reported the association of CSNK2A2 variants with leukocyte telomere length (Saxena et al. 2014). Further, the interaction of BPA with transforming growth factor-β (TGF-β receptor) I (where phosphorylation of a Gly-Ser regulatory region observed during activation) enabled us to consider transforming growth factor-β (TGF-β) signaling also as a potential target of BPA. Since it is a pleiotropic cytokine elicits complex effects in cells that plays key role in cardiovascular physiology, hemostasis, blood-vessel interface and malignancies (Kubiczkova et al. 2012; Redondo et al. 2012).