The tyrosine kinase

What is a tyrosine kinase?

Tyrosine kinase is a specific group of enzymes that are functionally assigned to protein kinases in a biochemical sense. Protein kinases reversibly (possibility of back-reaction) transfer phosphate groups to the OH group (hydroxy group) of the amino acid tyrosine. The phosphate group is transferred to the hydroxy group of the tyrosine of another protein. Through this reversible phosphorylation described above, tyrosine kinases can decisively influence the activity of proteins and therefore play an important role in signal transduction pathways. The function of tyrosine kinases as drug targets is used mainly therapeutically, e.g. in oncology.

The task and function

Tyrosine kinases must first be subdivided into membrane-bound and non-membrane bound tyrosine kinases in order to understand their function. Membrane-bound tyrosine kinases may have their own protein kinase activity, whereby kinase function is activated as part of the receptor complex on the cell membrane. Otherwise, membrane-bound tyrosine kinases may be functionally linked to the receptor complex, but may not be directly localized within it.

In this case, the tyrosine kinase and the receptor create a bond through which a specific signal is transmitted to the kinase via the receptor. In the case of a non-membrane bound tyrosine kinase, the kinase is located either in the cytoplasm or the nucleus of a cell. Depending on the structural design with associated function, different examples of tyrosine kinases can be given.

Examples of membrane-bound tyrosine kinases are the insulin receptor, the EGF receptor, the NGF receptor or the PDGF receptor. This shows that the signaling cascades using tyrosine kinases are vital processes in the human body. The insulin receptor regulates the release of insulin from the pancreas in connection with meals.

The EGF receptor has specific binding sites for several ligands, including EGF or TNF-alpha. As a protein ligand, the EGF (epidermal growth factor) plays a prominent role as a growth factor (cell proliferation and differentiation). TNF-alpha, on the other hand, is one of the strongest pro-inflammatory markers in the human body and plays an important diagnostic role in the diagnosis of inflammation.

PDGF in turn is a growth factor released by thrombocytes (blood platelets), which induces wound closure and, according to current research findings, also plays a role in the development of pulmonary hypertension. Examples of non-membrane bound tyrosine kinases are ABL1 and Janus kinases. In principle, a signaling cascade with specific information always proceeds in the same stereotypical manner in the case of a tyrosine kinase.

First, a suitable ligand must bind to a receptor, which is usually located on the surface of cells. This connection is usually established by a congruent protein structure of ligand and receptor (key-lock principle) or by binding to certain chemical groups of the receptor (phosphate, sulfate groups, etc.). The protein structure of the receptor is changed by the linkage.

Especially in tyrosine kinases, the receptor forms homodimers (two identical protein subunits) or heterodimers (two different protein subunits). This so-called dimerization can lead to an activation of tyrosine kinases, which, as already mentioned above, are located directly in the receptor or on the cytoplasmic side (facing the cell interior) of the receptor. Through activation, hydroxy groups of tyrosine residues of the receptor are linked to phosphate groups (phosphorylation).

This phosphorylation creates recognition sites for intracellularly localized proteins, which can subsequently bind to them. They do this via specific sequences (SH2 domains). After binding to the phosphate groups, highly complex signal cascades are triggered in the cell nucleus, which in turn leads to phosphorylation.

It should be noted that phosphorylation by tyrosine kinases can influence the activity of proteins in both directions. On the one hand, they can be activated, but on the other hand they can also be inactivated.Thus, it becomes apparent that a dysbalance in tyrosine kinase activity can lead to an over-stimulation of growth factor-associated processes, which ultimately leads to increased proliferation and de-differentiation (loss of cellular genetic material) of body cells. These are the classical processes of tumor development. However, defective regulatory mechanisms of tyrosine kinases also play a decisive role in the development of diabetes mellitus (insulin receptor), arteriosclerosis, pulmonary hypertension, certain forms of leukemia (especially CML) or non-small cell lung cancer (NSCLC).