Regulation and Function of Protein Kinase
There are about 500 protein kinase encoding genes in the human genome which represents 2% of all the human genes.
Kinase is the name given to an enzyme that adds a phosphate group (PO43-) to other biomolecules such as protein, lipid, or nucleotides. This type of addition of a phosphate group is called phosphorylation.
Opposite to these kinases are phosphatases. Phosphatase is an enzyme that is responsible for removing a phosphate group from a biomolecule. Thus phosphatase functions in opposition to the action of a kinase.
The known sources of the phosphate group of transfer are the high-energy compounds ATP or GTP. Kinases derive the phosphate group from these high-energy molecules and catalyze its addition to a target molecule. These enzymes are highly precise and target-specific.
The majority of the kinases are grouped as protein kinases (PTKs).
As the term suggests, these kinases are responsible for the covalent addition of phosphate groups in a protein. In protein targets, mainly the amino acids serine, threonine, and tyrosine in a peptide chain are phosphorylated.
There are certain kinases that bind to both serine and threonine, and are called serine/threonine kinases, having dual specificity.
The phosphorylation of any of these amino acids leads to a conformational change in the protein structure thereby leading to protein activation. Such activation is essential for proteins to function in the cell.
In 1992, Edmond H. Fischer and Edwin G. Krebs were awarded the Nobel prize “for their discoveries concerning reversible protein phosphorylation as a biological regulatory mechanism”. This brought about the importance of protein phosphorylation.
Phosphorylation is considered to be the most common protein modification used in signal transmission. As signaling enzymes, protein kinases play a critical role in cellular signal transduction as they orchestrate various intracellular processes like ion transport, subcellular trafficking, glycogen synthesis, apoptosis, and hormone response.
Thus, we can say that protein kinases are enzymes that regulate the biological activity of proteins.
Protein kinases are classified in two ways:
- Based on the catalytic domain: CAMK kinase, AKT kinase, MAPK, PKA kinase, CK 1 kinase
- Based on substrates: Tyrosine Kinase, serine-threonine kinase, and histidine kinase
In this article, we will cover the importance and application of protein kinases along with a brief discussion on tyrosine kinase.
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Kinase Uses and Functions
Kinase are among the most important family of enzymes as they are essential in the functioning of our biological system. They are useful in many domains of biochemical study of cellular processes and have varied functions.
In Drug Discovery
Since protein kinases are involved in protein modulation, they take part in cellular processes like antibody formation in B cells, glucose metabolism, cell cycle regulation, growth, and proliferation.
Any abnormal activity of these protein kinases can lead to diseases like autoimmune disorders, diabetes, or cancer like leukemia. Therefore, protein kinases are a highly targeted family when it comes to disease pathophysiology, and drug discovery.
To target and modulate protein kinase activity, drugs are designed as small molecule inhibitors of protein kinases.
In case of abnormality or mutations, inhibition of protein kinase prevents overexpression, signaling proteins and altering the biochemical activity of kinase.
This approach has brought about remarkable successes in clinical research and cancer drug discovery.
PDK1 (Phosphoinositide-dependent kinase 1) is a major regulator of at least 23 AGC kinases. In addition, the stimuli used in controlling the activity of protein kinase can also be used to regulate protein phosphatase activity.
Researchers with expertise in molecular and cell biology have been involved in studies involving how kinase signal transduction works because this understanding will help solve the cause and consequences of the disruption of regulation in protein kinases.
This will help formulate drugs that will target cancer cells and immune cells for treating diseases like cancer and inflammatory conditions.
In vitro study of animal models has shown the importance of AMPK, IKK, and PKC in fatty acid oxidation, insulin sensitivity, and glucose metabolism.
In Cellular and Molecular Toxicology
In pathophysiological processes, toxicological agents play an important role in regulation of protein kinases.
Kinase activity is dependent on the concentration of toxicant concentration. Toxicants have a different toxicological profile at low and high concentrations. Protein Kinase C (PKC) is a perfect example of regulation of protein kinase by toxicant gradient. A toxicant acts as a kinase inhibitor.
Based on the concentration of the toxicant, the activity of the protein kinase can be modulated. Lower levels show increased activity and higher levels show decreased activity of the protein kinase. Such regulations can be direct or indirect and can be associated with multikinase targeting.
Therefore, protein kinase holds application in the field of cellular and molecular toxicology too.
Cellular Activation Processes and Signal Transmission
Protein kinases are intracellular enzymes that bind phosphate to side chains of serine, threonine, or tyrosine residues.
Such binding initiates different types of intracellular responses and transmission of cellular signals to conduct processes like cell growth, metabolism, transcription, proliferation, and immune modulation and signaling cascades.
The primary means of signal transduction is phosphorylation. Typical signal transduction comprises the activation of a pre-existing protein by phosphorylation as post translational modification. Second is the production of a new protein.
This leads to activation of specific pathways. For instance, the Ras-Raf-MEK-ERK pathway is a result of Raf kinase activity.
Signal transduction results in a cellular response. Protein kinase like the Calcium-dependent Protein Kinase (CDPKs) is involved in the ABA (Abscisic acid) signaling in plants which come under hormone signaling. CPK4 and CPK11 regulate ABA signaling through transcription factors.
Receptor Tyrosine Kinase
The most common kinase family is receptor tyrosine kinase (RTK), classified by the substrate it attaches to. It is a protein receptor that carries out phosphorylation.
In a cell, RTKs are embedded in the plasma membrane and it consists of 2 subunits:
- The intracellular part consists of tyrosine amino acid residues, thus the name tyrosine kinase.
- On the extracellular part, there is a ligand-binding site where the signaling molecule comes and binds.
Once the signaling molecule, usually a growth factor, binds to the active site of the receptor, it causes neigboring RTKs to associate to each other. Once cross-linked, this activates the tyrosine kinase activity in each of the associated RTKs. These tyrosine kinase subunits then phosphorylate each other.
The further phosphorylation of relay proteins by RTKs activates a cascade of signaling transduction pathways leading to a cellular response.
- RTKs are important mediators of various signal transduction mechanisms.
- RTKs can initiate multiple cellular responses only with the binding of a single ligand.
- RTKs activate cellular responses like cell proliferation, differentiation, metabolism and programmed cell death.
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Protein kinases are a large family of enzymes that catalyze the addition and localization of phosphate groups to the amino acids in the peptide chains of proteins, a process known as protein phosphorylation. Protein phosphorylation is one of the initial steps in the coordination and control of most cellular functions.
Protein kinases are highly essential as they play a vital role in initiating and processing these signaling pathways in a cell. As a result, the knowledge of their functions and regulation mechanisms are pivotal in studying drug discovery and molecular toxicology.
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