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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In order to control the effects of kinase activation on cellular processes for therapeutic purposes, a number of strategies have been pursued. First, use can be made of the opposing effects of different protein kinases. For example, activation rather than inhibition of some kinases can lead to cellular growth inhibition or cell death (e.g., activation of transforming growth factor-β [TGF-β] receptor signal transmission can invoke cell-cycle arrest). Second, activation of protein phosphatases that remove phosphates from kinase residues may switch off kinase signaling. Third, reducing or blocking the activity of enzymes involved in the formation of protein ligands, or activating specific protease enzymes that degrade the ligands may modify signaling. Finally, the function of protein kinases can be directly manipulated by therapeutic agents. By far the most productive method of manipulation to date has involved the development of small molecules to interact in the ATP-binding pocket of individual kinases (e.g., imatinib), and most of the kinase inhibitors described below work through this mechanism. Alternatively, antibodies can be used to bind to the extracellular domain of receptor membrane kinases (e.g., trastuzumab), thereby blocking signaling, and this approach is described in Chapter 9.
Fetal Growth Factors*
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
Philip A. Gruppuso, Thomas R. Curran, Roderick I. Bahner
A discussion of regulation by protein phosphorylation should include a discussion of protein phosphatases. Study of protein phosphatases has lagged behind that of kinases, but the last several years have seen rapid advances. Protein phosphatases can be divided into two broad categories: serine/threonine vs. tyrosine specific.64,65 Within each category there is broad diversity which is comparable to that of the protein kinases. Protein phosphatase regulation has long been known to be centrally involved in metabolic regulation; the first demonstration of the interconversion of an enzyme between active and inactive forms was the inactivation (through dephosphorylation) of glycogen phosphorylase by phosphorylase phosphatase. The importance of the phosphatases in regulation of cellular processes is certainly comparable to that of kinases. Insulin effects are mediated in large part by the dephosphorylation of target enzymes.64 Recent work has demonstrated the involvement of protein phosphatases in cell cycle progression.63
Signal Transduction Mechanisms Regulating Cytokine-Mediated Induction of Acute Phase Proteins
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Okadaic acid (OA), an inhibitor of protein phosphatases 1 and 2A, has served as a valuable tool for evaluating the role of protein phosphatases in several cellular functions. Examination of the effect of OA on the induction of acute phase proteins by the cytokines IL-6 and IL-1 in Hep 3B and NPLC/PRF/5 cells revealed that 49 (1) in Hep 3B cells, OA inhibited the induction of CRP, SAA, and fibrinogen by IL-6 plus IL-lα, and of fibrinogen by IL-6 alone in a concentration-dependent manner (5 to 20 nM) (Figure 5A), and (2) in NPLC/PRF/5 cells, OA inhibited the induction of CRP, fibrinogen, and α1-PI by IL-6, albeit at a higher concentration (20 to 80 nM) (Figure 5B). The induction of CRP by IL-6 plus IL-lα was most sensitive to the inhibitory effect of OA; a concentration of 10 nM OA in Hep 3B cells and 40 nM in NPLC/PRF/5 cells led to almost complete inhibition of the induction of CRP, whereas induction of other acute phase proteins was inhibited by only 40 to 60%. In Hep 3B cells, concentrations of OA above 20 nM were toxic and OA below this concentration had no significant effect on the induction of α1-PI by IL-6 plus IL-lα or IL-6 alone.
Ser69 phosphorylation of TIMAP affects endothelial cell migration
Published in Experimental Lung Research, 2021
Nikolett Király, Csilla Csortos, Anita Boratkó
In pulmonary endothelial cells, two major Ser/Thr-specific phosphatases, protein phosphatase (PP) type 1 and type 2 A (PP1 and PP2A) were shown to be crucial in maintaining the EC cytoskeleton, adherent junctions and barrier function.5–8 The extremely high versatility of these phosphatases is due to their multi-subunit holoenzyme structure. Phospho-Ser/Thr-specific protein phosphatases consist of a catalytic subunit that reversibly binds to further regulatory or interacting partner proteins which control the enzymatic activity by targeting the holoenzyme to specific subcellular locations and substrates. PP1 holoenzymes are usually heterodimers, a large number of regulator proteins may target the activity of the four isoforms of PP1 catalytic subunits (PP1c α, PP1c β/δ, PP1c γ1, PP1c γ2).2
Inhibition of protein phosphatase-1 and -2A by ellagitannins: structure-inhibitory potency relationships and influences on cellular systems
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Zoltán Kónya, Bálint Bécsi, Andrea Kiss, Dániel Horváth, Mária Raics, Katalin E. Kövér, Beáta Lontay, Ferenc Erdődi
It is now well accepted that the phosphorylation of proteins is an important regulatory device in many cellular processes and it is regulated by not only the phosphorylating protein kinases but the dephosphorylating protein phosphatases as well1. Protein phosphatase-1 (PP1) and -2 A (PP2A) are two major representatives of the phosphoserine/threonine (P-Ser/Thr) specific enzymes and they are believed to be responsible for the dephosphorylation of more than 90% of P-Ser/Thr side chains in cellular phosphoproteins2. PP1 and PP2A occur in cells in many holoenzyme forms in which the catalytic subunits (PP1c and PP2Ac) are associated with distinct regulatory proteins. The three major isoforms (α, β/δ, and γ) of PP1c (PPP1CA, PPP1CB, and PPP1CG) may be complexed to close to 100 regulatory proteins which generally include a PP1c-interacting sequence termed the RVxF motif3. In the PP2A holoenzymes the core unit consists of PP2Ac (PPP2CA or PPP2CB) and a 65 kDa A subunit (termed PP2A-AC) and this dimer is associated with distinct classes of B subunit forming various trimer holoenzymes (PP2A-ABC)4.
Current status of sperm functional genomics and its diagnostic potential of fertility in bovine (Bos taurus)
Published in Systems Biology in Reproductive Medicine, 2018
Sellappan Selvaraju, Sivashanmugam Parthipan, Lakshminarayana Somashekar, B. Krishnan Binsila, Atul P. Kolte, Arunachalam Arangasamy, Janivara Parameshwaraiah Ravindra, Stephen A. Krawetz
CALM, protein kinase catalytic subunit alpha (PRKACA), and serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC) were identified as network partners of the insulin signaling pathway with an FDR 0.02 and regulating the resumption of oocyte meiosis (FDR, 0.01). PPP1CC is known for dephosphorylation of several regulatory proteins during cell division. During insulin signaling, the active form PPP1CC inactivates the calcium/calmodulin-dependent protein kinases by dephosphorylation and promotes glucose metabolism. The interaction of insulin (INS) or insulin-like growth factor 1 (IGF1) with its receptor on the oocyte membrane triggers the activation of PRKACA. In turn, this promotes the early translation of maternal transcripts necessary for MAPK signaling and ubiquitin-mediated proteolysis during oocyte meiosis. The PPP1CC also activates the CDC25C, that initiates the transition from mitosis to meiosis-I by dephosphorylating CYCB2/B5 and CDC2 (McHughes et al. 2009) as required for the embryo pattern formation and morphogenesis (De Faria Poloni et al. 2011). In mammals, when the sperm penetrates the oocyte, a signal transduction mechanism is triggered by the PLCz1 cascade. CALM is one of the regulatory proteins that activate PTW/PP1, serine/threonine-protein phosphatase that ensures meiosis-II completion. It maintains chromatin structure during the transition from mitosis to interphase (Lee et al. 2010).