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Intracellular Kinases and Signal Transduction


Introduction of Kinase

Intracellular Kinases and Signal Transduction

Kinase is a kind of enzyme which can catalyze the transfer of phosphate groups from high-energy, phosphate-donating molecules (like ATP) to specific substrates. This process is known as phosphorylation, where the substrate gains a phosphate group and the high-energy molecule donates a phosphate group. This procedure produces a phosphorylated substrate and ADP. Conversely, there is also a procedure for those phosphorylated substrates to remove phosphate group to produce a dephosphorylated substrate and the high energy molecule of ATP, which is called dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. Kinases are part of the larger family of phosphotransferases. The phosphorylation state of a molecule can affect its activity, reactivity, and its ability to bind other molecules. Therefore, kinases are of great significance in metabolism, cell signaling, protein regulation, cellular transport, secretory processes, and many other cellular pathways, which makes them very important to human physiology.

Classification of Kinase

Kinases can be divided into three groups by the substrate they act on, including protein kinases, lipid kinases, and carbohydrate kinases.

Protein Kinases

Protein kinases are an important class of intracellular enzymes that play a crucial role in most signal transduction cascades, from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Protein kinases, also referred to as phosphotransferases, phosphorylate their target proteins in cells by attaching phosphates covalently to the side chains of serine, threonine or tyrosine residues. Kinases have subsequently been shown to play an imperative role in the first step of intracellular immune cell signaling. For example, kinases are associated with the intracellular component of receptors on the cell surface of T and B lymphocytes, and initiate intracellular signaling cascades within these cells once such receptors have engaged with their extracellular ligands. As it was established that protein kinases were the fundamental drivers of inflammatory cell signaling, they were investigated as therapeutic targets for a variety of diseases.

Protein kinases mediate the transfer of the γ-phosphate (P) from adenosine triphosphate (ATP) to the hydroxyl group (OH) of a serine, threonine or tyrosine residue of the targeted protein. This phosphorylation acts as a ‘molecular switch’, which directly activates, or inactivates the functions of proteins. However, protein phosphatases can oppose the kinase activities and reverse the effects of phosphorylation, by catalyzing the removal of the γ-phosphate from the targeted protein.

According to previous study, more than 400 diseases have been associated either directly or indirectly with protein kinases. Thus protein kinases are now considered to be one of the most important groups of drug targets. Kinases can be targeted by small molecular compounds which act to inhibit the phosphorylation of proteins, thus preventing their activation. These small molecule inhibitors can interfere with kinase activity by blocking adenosine triphosphate (ATP)-kinase binding, interfering with kinase–protein interactions, and down-regulating kinase gene expression levels.

There are three kinds of protein kinase targets, namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (SYK).

Lipid Kinases

As for lipid kinases, the most typical one is phosphoinositide kinases related to lipid phosphoinositides. Lipid phosphoinositides are essential mediators of many membrane signaling events, and their spatiotemporal location in a cell must be tightly regulated. Phosphoinositides have key functions in directional membrane trafficking, recruitment of signaling machinery to specific phosphoinositides, mediating lipid transport across a gradient, regulation of ion channels, and many others. Phosphoinositides are generated by the regulated activity of both phosphoinositide kinases and phosphatases. Phosphoinositide kinases and phosphatases can be recruited sequentially in membrane trafficking pathways to generate specific phosphoinositides. Dysregulation of phosphoinositide kinases, primarily in the class I phosphoinositide 3-kinases (PI3Ks) that generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), has been discovered in a number of human diseases, with mutations leading to either increased or decreased enzymatic activity being critically involved in cancer, developmental disorders, and primary immune deficiencies. While other phosphoinositide kinases are not frequently mutated in disease, they are still involved in myriad diseases and have been found to play key roles in mediating infection of a variety of viral and bacterial pathogens. With the key role of many of these phosphoinositide kinases in disease, there has been extensive work applied to the development of small molecule inhibitors.

Carbohydrate Kinases

Carbohydrates kinases play an important role in almost all metabolic pathways. In the process of glycolysis, two important reactions are catalyzed by carbohydrates kinases, including Hexokinase and Phosphofructokinase. When Hexokinase enters the cell, it can convert D-glucose to glucose-6-phosphate by transferring the gamma phosphate of an ATP to the C6 position. Through the phosphorylation, it traps glucose inside the cell. Glucose can move across the membrane by being dephosphorylated. If there are mutations in the hexokinase gene, it can lead to a hexokinase deficiency and cause nonspherocytic hemolytic anemia. Phosphofructokinase, or PFK, also regulates the process of glycolysis through catalyzing the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Besides, mutation in the PFK gene will lead to the reduction of activity of PFK, resulting a very rare disease named Tarui's disease, a glycogen storage disease that leads to exercise intolerance.

Above all, there are still some kinases that act on many other substrates, including those involved in nucleotide interconverstion, such as nucleoside-phosphate kinases and nucleoside-diphosphate kinases. Besides there are also substrates of kinases including creatine, phosphoglycerate, riboflavin, dihydroxyacetone, shikimate, etc.

Thymidine Kinase

Thymidine kinase 2(TK2) catalyzes the transfer of the γ-phosphate group from ATP to the 5′-hydroxyl group of thymidine (dT), deoxycytidine (dC), or deoxyuridine (dU) to form their corresponding monophosphates. TK2 also phosphorylates a number of pyrimidine nucleoside analogues, such as zidovudine (AZT) used in anti-HIV therapy. TK2 can be used in antiviral and anticancer therapies by mitochondrial toxicity. TK2 is present in all cells that contain mitochondria, and the levels of TK2 are related to the mitochondrial content of the cells or tissues. Deficiency in TK2 activity due to genetic mutations causes devastating mitochondrial diseases, which are characterized as tissue-specific mtDNA depletion and/or deletion. Mitochondrial DNA depletion syndrome (MDS) is characterized by a severe and tissue-specific reduction in the mtDNA copy number in the absence of qualitative defects in mtDNA. MDS caused by TK2 mutations mainly affects liver and skeletal muscle, but in some cases, multiple tissues are involved. Mutations in the TK2 gene are also the genetic causes of late-onset autosomal recessive progressive external ophthalmoplegia.

References:

  1. H. Patterson, R. Nibbs, I. McInnes, S. Siebert. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clinical and experimental immunology. 2013, 176: 1-10.
  2. John E. Burke. Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease. Molecular Cell. 2018, 71: 653-673
  3. Ren Sun, Liya Wang. Thymidine Kinase 2 Enzyme Kinetics Elucidate the Mechanism of Thymidine-Induced Mitochondrial DNA Depletion. Biochemistry. 2014, 53: 6142-6150.

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