Overview of Mechanisms for Coupling of Receptor-Agonist Interactions With Physiological Effects
John C. Matthews in Fundamentals of Receptor, Enzyme, and Transport Kinetics, 2017
Many membrane-associated receptor systems initiate their physiological effects through cyclic nucleotide-stimulated protein kinases or through direct stimulation of protein kinases without the requirement for the cyclic nucleotide intermediates. The best understood of these are the adenylate cyclase systems. Adenylate cyclase is an enzyme associated with the inner surface of the plasma membrane of many cells. Adenylate cyclase converts ATP to cyclic AMP. Cyclic AMP interacts with its receptor, a protein kinase enzyme, to activate it. The protein kinase then catalyzes the transfer of a phosphate group from ATP to a hydroxyl group of another enzyme or protein, to activate or inactivate that protein. The protein, which becomes phosphorylated by the action of the protein kinase, is invariably an important component of the physiological process being regulated. Its phosphorylation can either turn on or turn off (or, more likely, speed up or slow down) that entire physiological process.
Protein Phosphorylation
Enrique Pimentel in Handbook of Growth Factors, 2017
Phosphorylation of cellular proteins on serine and threonine is more common than the phosphorylation on tyrosine residues. Hormones and growth factors, as well as oncoproteins and tumor promoters, can stimulate the phosphorylation of cellular proteins not only on tyrosine but also on serine and threonine residues, and this modification may be important for regulating the functional activity of the substrates. Distinct types of serine/threonine-specific protein kinases (serine/threonine kinases) are involved in such phosphorylations.483 These enzymes depend on either activation of the adenylate cyclase system (cAMP-dependent protein kinases) or activation of other types of protein kinases (cAMP-independent protein kinases), the latter including Ca2+-phospholipid-dependent protein kinase (protein kinase C).484 A unique type of serine/threonine kinase is the DNA-activated protein kinase (DNA-PK), which requires double-stranded DNA for activity in vitro and may have a role in DNA transcription as well as in DNA replication, recombination, and/or repair.485 Many DNA binding proteins, including a number of transcription factors, are substrates for DNA-PK in vitro. Phosphorylation of serines by DNA-PK in the amino-terminal transactivation domain of DNA-bound p53 protein may alter p53 function, thus contributing to the regulation of cellular proliferation.486
The Neonatal STZ Model of Diabetes
John H. McNeill in Experimental Models of Diabetes, 2018
The signal transduction pathway of insulin involves a series of phosphorylation and dephosphorylation steps, which ultimately leads to a change in the phosphorylation state and function of specific target proteins (see Figure 11.1). Therefore, it is not surprising that the activity of several of the key protein kinases and phosphatases are affected by diabetes (see Table 11.4). Although a direct link has not yet been established between changes in the phosphorylation state of specific proteins and the development of contractile defects in the n2 STZ heart, the use of various agonists suggest that the two parameters are related. Of particular interest is the observation that the positive inotropic effect of the β-adrenergic agonist isoproterenol is significantly depressed in the n2 STZ heart (Figure 11.10). Since activation of protein kinase A is unaffected by the diabetic condition,61 it is likely that the responsiveness of the target protein to the phosphorylation event must be defective in the n2 STZ heart. Whether the primary abnormality involves a Ca2+ transporter or a contractile protein still remains to be established.
A comprehensive review of protein kinase inhibitors for cancer therapy
Published in Expert Review of Anticancer Therapy, 2018
Radhamani Kannaiyan, Daruka Mahadevan
Ever since the first phosphorylation reaction was identified in glycogen metabolism and glycogen phosphorylase was identified in the 1960s, kinases have been of interest to scientists. A protein kinase is an enzyme that modifies other proteins by chemically adding the terminal γ-phosphate group of adenosine triphosphate to serine, threonine, or tyrosine residues which is also known as phosphorylation. Phosphorylation results in a functional change of the target protein (substrate) by regulating signaling pathways by amplification (common) or cellular location, or by interactions with regulatory proteins. Human genome sequencing has revealed that about 2% of the human genome encodes for protein kinases [1,2]. They are further subdivided into groups, families and subfamilies (Figure 1). There are >500 protein kinases known and the structures of these kinases in various conformations have been determined by X-ray protein crystallography [2]. Kinases are involved in various cellular functions including metabolism, cell cycle regulation, survival, and differentiation. Once activated kinases typically phosphorylate serine, threonine, or tyrosine residues on the target protein, leading to conformational change and thereby the functionality of the target proteins [3]. Please see Figure 1 for the human kinome represented as a phylogenetic tree as listed in the scientific database.
Natural products as novel scaffolds for the design of glycogen synthase kinase 3β inhibitors
Published in Expert Opinion on Drug Discovery, 2022
Serena Montanari, Claudia Seidl, Lara Davani, Eleonora Gianquinto, Eliska Emrichova, Cristina Terenzi, Vincenza Andrisano, Angela De Simone
Most aspects related to cell life are regulated by protein kinases. That is why some mutations or changes in their genes are closely related to cancer and other diseases. In the twenty-first century, GSK-3β has emerged as one of the most attractive therapeutic targets involved in unmet severe pathologies. Although the first role assigned to this kinase concerns its involvement in the regulation of glycogen metabolism, many other roles in pathologies such as Alzheimer’s Disease (AD), frontotemporal dementia, type 2 diabetes, bipolar disorders, stroke, other tau pathologies as well as cancer and inflammation have been attributed to this kinase [1]. Undeniably, it controls many cellular processes such as gene transcription and neuronal cell functions, as well as embryonic development, where it plays a fundamental role in the Wnt signaling pathway [2]. For all these roles, it can be considered as a cellular nexus connecting several signaling systems, including a wide range of second messengers and cellular stimulants.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
It is well known that ATP is the primary carrier of energy in cells. Upon hydrolysis, it releases energy from the chemical bonds to fuel cellular processes. For example, ATP hydrolysis by motor proteins or DNA helicases can induce conformational changes and thus drive the translocation of these proteins. In addition, the protein kinases regulate various biological processes by transferring a phosphate group from ATP to amino acid residues like serine, threonine, or tyrosine. Interestingly, the mitotic kinases Aurora B, Haspin, and Bub132 also possess intrinsic ATPase activity, producing free inorganic phosphate. It is currently unknown whether this energy-consuming activity has a physiological role in cells, further studies are needed to address this potentially interesting question.
Related Knowledge Centers
- Bacteria
- Catalysis
- Genome
- Phosphate
- Protein Phosphorylation
- Signal Transduction
- Kinase
- Substrate
- Serine/Threonine-Specific Protein Kinase
- Tyrosine Kinase