Non-Receptor Tyrosine Kinase Signaling

Non-receptor tyrosine kinases (NRTKs), which can activate intracellular signals generated from external receptors, are a subset of tyrosine kinases, intracellular cytoplasmic proteins, or tethered to the cell membrane. Based mostly on similarities in the kinase domain sequences, they can be divided into nine subfamilies. These are the kinases from the ABL, FES, JAK, ACK, SYK, TEC, FAK, SRC, and CSK families.

NRTKs, which have a great deal of structural variety, don’t have receptor-like characteristics such as an extracellular ligand-binding domain or a transmembrane-spanning domain. They are made up of a large cytoplasmic C-terminal region and an N-terminal section of a common kinase domain that spans around 300 residues. Additionally, they frequently contain a number of extra SH2, SH3, and PH domains, which are signaling or protein-protein interaction domains. The protein substrate’s tyrosine sequence interacts with the residues of the C terminal domain by the binding of the ATP molecule between the two domains.

NRTK Signaling

Recent structural research on receptor tyrosine kinases (RTKs) has found unanticipated variations in the ways that growth factor ligands activate these enzymes. Both methods for triggering dimerization by ligand binding and those connecting this action to the activation of intracellular tyrosine kinase domains are surprisingly varied. It provides a crucial background for therapeutically reversing the impact of pathogenic RTK mutations in cancer and other disorders as our knowledge of these specifics gets more detailed. However, there is still much to understand about the intricate signaling networks connected to RTKs and how changes in these networks result in cellular reactions.

The transfer of a phosphate group from a nucleoside triphosphate donor, such as ATP, to tyrosine residues in proteins is catalyzed by a cytosolic enzyme known as a non-receptor tyrosine kinase (nRTK). Protein family tyrosine kinases, which are enzymes that can transfer the phosphate group from ATP to a tyrosine residue of a protein, include a subgroup known as non-receptor tyrosine kinases (phosphorylation). These enzymes control a variety of biological processes by activating or deactivating different enzymes within a cell.

NRTK Pathway

Phosphate groups are added to tyrosine residues on protein substrates by enzymes known as protein tyrosine kinases (PTKs). Proteins can alter in function and/or enzymatic activity by phosphorylation, and these changes trigger particular biological reactions. PTKs are divided into two classes: cytoplasmic non-receptor PTKs and transmembrane receptor PTKs (NRTKs). NRTKs participate in the transmission of extracellular signals, which frequently interact with transmembrane receptors. As a result, they play a crucial role in signaling pathways that control essential biological processes such as cell differentiation, death, survival, and proliferation. The activity of NRTKs is closely controlled, and overexpression or deregulation of NRTKs has been linked to cancer development and malignant transformation.

The mechanics of numerous cellular processes, including those implicated in carcinogenesis, have been clarified through research on NRTKs. It should come as no surprise that a number of tyrosine kinase inhibitors are currently being used to treat a variety of cancers, and others are being researched. The nine major families of NRTKs and their signaling pathways in both healthy and malignant cells are the topics of this review.

Regulation

Post-translational modifications include tyrosine phosphorylation, which is carried out by protein tyrosine kinases (PTKs). Five members of the Tec kinases subfamily of non-receptor PTKs were first identified in the hematopoietic system: Tec, Btk, Itk/Emt/Tsk, Etk/Bmx, and Txk/Rlk. As modern research has advanced, it has been discovered that some members of the Tec family of kinases are expressed outside the hematological system and are involved in the onset and development of a number of disorders. More research is being done on the involvement of Tec family kinases in cardiovascular disease. Ischemic heart disease, atherosclerosis, sepsis-associated cardiac dysfunction, atrial fibrillation, myocardial hypertrophy, coronary atherosclerotic heart disease, myocardial infarction, and post-myocardial necrosis are all caused by and progressed by tec kinases.

The function of Tec kinases in the cardiovascular system hasn’t, however, been thoroughly explained in any reviews. Consequently, this review highlights research on the function of Tec kinases in cardiovascular disease, offering fresh perspectives on its prevention and treatment.

Difference between RTK and NRTK

RTK	NRTK
The transmembrane domain is typically present in the receptor kinase protein.	The non-receptor tyrosine kinase, however, is transmembrane domain-deficient.
Have growth factors	Inhibition of cell growth
Mediates the movement of the phosphate group to tyrosine residues of the target protein.	Non-receptor TKs are intracellular cytoplasmic proteins that relay intracellular signals.
RTKs are a group of 90 families.	It is a group of 9 subfamilies.

Functions of NRTK Signaling

• NRTKs are important in the transmission of signals originating from extracellular cues, which commonly interact with transmembrane receptors. 
• As a result, they play a crucial role in signaling pathways that control essential biological processes such as cell differentiation, death, survival, and proliferation.
• The activity of NRTKs is closely controlled, and carcinogenesis and malignant transformation have been linked to the deregulation and/or overexpression of NRTKs.
• The mechanics of numerous cellular processes, including those implicated in carcinogenesis, have been clarified through research on NRTKs. 
• Proteins can alter in function and/or enzymatic activity by phosphorylation, and these changes trigger particular biological reactions. 
• NRTK signaling help in the activation of T and B lymphocytes.

FAQs on NRTK Signaling

Question 1: What is the main role of phosphate groups in Non-Receptor Tyrosine Kinase Signaling?

Answer:

Tyrosines on the receptor tails that are phosphorylated cause the formation of an intracellular signaling complex on the tails. Tyrosines that have recently undergone phosphorylation act as binding sites for signaling proteins, which subsequently transmit the information to additional proteins.

Question 2: How does nonreceptor tyrosine kinase(NRTK) signaling work?

Answer:

The subgroup of tyrosine kinases called non-receptor tyrosine kinases (NRTK) can transmit intracellular impulses from external receptors. Numerous biological processes, including cell survival, division/propagation, adhesion, gene expression, immunological response, etc., can be controlled by NRTKs.

Question 3: How does receptor tyrosine kinases are regulated?

Answer:

Controlling the ligand’s access to the receptor is one of the main ways receptor tyrosine kinase (RTK) signaling is regulated. Transmembrane proteins are the building blocks for many RTK ligands. Frequently, signaling cannot start until the active ligand has been liberated from the membrane by proteolysis.

Question 4: Where does the non-Receptor Tyrosine Kinase (nRTK) locate?

Answer:

NRTKs lack receptor-like characteristics such as an extracellular ligand-binding domain and a transmembrane spanning region, in contrast to receptor tyrosine kinases. The majority of nRTKs are found in the cytoplasm, however, some of them can be modified at their amino termini to bind them to the cell membrane.

Question 5: Define protein tyrosine kinases(PTK) enzymes.

Answer:

Proteins known as protein kinases are able to chemically combine substrate proteins that contain phosphate groups. They play significant parts in controlling a variety of biological processes, from energy metabolism to cell cycle development.