Protein kinases

Protein kinases represent a separate family of kinases. Kinases are enzymes that form the second most common class of proteins in higher cells. Protein kinases are enzymes which act as substrates for alcoholic amino acid residues of proteins. There are 7 main groups of protein kinases known with > 500 human protein kinases.

Among the protein kinases there are multifunctional enzymes that phosphorylate numerous protein substrates and highly specific protein kinases that can only phosphorylate a single protein. The effect of these kinases can be reversed by specialized protein phosphatases(hydrolases). Protein kinases (as well as their antagonists the protein phosphatases) are important regulators of cell function. Thus, they are essential in signal transduction and the coordination of complex functions such as the cell cycle.

The first step in signal transduction is the activation of the kinases themselves; this step is ultimately not yet fully understood. It is likely that a conformational change in the protein structure of the receptors after ligand binding plays a decisive role in the activation.

The enzymatic phophorylation (function of the kinases) of a protein is - as well as its dephosphorylation (by phosphatases) - an irreversible, carefully controlled reaction.

The introduction of a phosphate group with its two negative charges changes the electrostatic conditions locally. This results in significant conformational changes that alter the biological activity of the substrate protein. If this protein is also a protein kinase, enzyme cascades with a great amplification effect occur.

Such protein-kinase cascades are frequently used in signal transduction. In principle, only side chains of amino acids are suitable as target groups for kinases. About 90% of all phosphorylations concern the amino acids serine and threonine (enzyme=serine-threonine kinases) and only 1% concern the amino acid tyrosine (enzyme=tyrosine kinases).

Protein kinases are either named according to the type of modified group (serine, threonine, tyrosine: serine kinases, threonine kinases, tyrosine kinases), or they are subdivided according to their activation mechanism (e.g. protein kinase A, protein kinase B, protein kinase C, protein kinase G). In principle, the structure of the protein kinases shows a similar structure. They are formed from 2 parts of a molecule, which are linked by a short polypeptide. The upper part consists of a beta-folded structure. The lower, predominantly alpha-helical part contains the substrate binding site. ATP, for example, binds in the deep gap between these molecular parts. Common to the protein kinases is the function of a switch, which can be in active or inactive form.

Examples of functionally important protein kinases:

• Serine/threonine protein kinases: They form by far the largest group of enzymes (with various subfamilies) generally associated with signal transduction in the cytoplasm. The following kinases belong to this kinase family:
• Checkpoint kinases CHK1, CHK2: Checkpoint kinases: The protein kinases CHK1 and CHK2 (checkpoint kinase 1/2) are encoded by the genes of the same name (CHEK1/2) on chromosome 11 q24.2, or on chromosome 22 q12.1). Both checkpoint kinases belong to the serine/threonine kinases. If CHK1 is activated during the S phase of the cell cycle, this activation prevents the transition to the G2 phase. This can contribute to the survival of tumor cells and therefore to their resistance to therapy. CHK2 was originally identified as a cell cycle regulating kinase. The kinase is involved in DNA repair.
• Type A protein kinase: The type A protein kinase (PKA), is a cAMP-dependent intracellular serine/threonine kinase, which is involved in numerous reactions of the energy metabolism. When 4 cAMP bind to the regulatory unit of the PKA, the active catalytic subunits are released, which are bound to the different PKA regulatory units. The active catalytic subunits are released, which catalyze the phosphorylation of the various proteins, including MAP kinases and transcription factors such as NF-κB.
• Protein kinase type B (PKB, protein kinase Akt): PKBs are serine/threonine protein kinases that are activated by phosphorylation. Type B protein kinase is involved in the regulation of central metabolic pathways, e.g. insulin action. PKBs are also effectors of the phosphoinositol pathway. The inactive kinases are found in the cytoplasm.
• Protein kinase type C (PKC): PKCs are zinc-containing serine/threonine protein kinases that are activated by the second messenger DAG. PKCs occur in at least 11 isoforms, which also differ in their functions. By binding to DAG, they are fixed to the plasma membrane. Their interaction with phospholipids requires Ca2+- ions. The membrane association of PKC is promoted by special membrane proteins called receptors for activated protein kinase C (RACK proteins). The activity of PKC is controlled by hormones and neurotransmitters, whose signal is transmitted via secondary messengers. The target molecules include MAP kinases and transcription factors such as NF-κB. Protein kinase C can again phosphorylate receptors, channels and other functional proteins and thereby control their activity.

• MAP kinases: MAP stands for "mitogen-activated protein", belong to the class of protein kinases and here again to the serine/threonine kinases. They phosphorylate proteins at serine or threonine residues. MAP kinases are part of highly conserved signalling cascades which, among other things, decisively control cell growth, differentiation and apoptosis.

  ERK: The protein kinase ERK (ERK stands for "extracellular-signal regulated kinases") and is a serine/threonine kinase belonging to the group of mitogen-activated protein kinases (MAP kinases). There are 8 isoforms of ERK.

• Tyrosine protein kinases: Tyrosine protein kinases are mostly membrane receptors and are formed by external ligand binding (receptor tyrosine kinases). But also cytoplasmic tyrosine kinases are known (so-called non-receptor tyrosine kinases).
• Receptor tyrosine kinases are membrane proteins that have a ligand-directed, intrinsic enzyme activity. Known are > 50 receptor tyrosine kinases. Ligands are for example insulin, the epidermal growth factor EGF and the platelet growth factor PGDF. Further ligands are: fibroblast growth factor, insulin-like growth factor IGF1/IGF2, nerve growth factor, PDGF (platelet growth factor) and transforming growth factor alpha (TGF-α).
• Receptors with associated protein tyrosine kinases: Erythropoietin, the interferons alpha, beta and gamma, the interleukins 1-7,9,12,15, tumor necrosis factor (TNF), growth hormone (GH) serve as ligands. These peptides have no kinase activity, but contain one or more motifs known as ITAM (immunoreceptor tyrosine activation motif).
• Protein kinases with double specificity (serine/threonine and tyrosine): These kinases form only a small group, to which MEK1 belongs.
• Histidine and asparagine kinases: Protein kinases that phosphorylate other amino acids, namely histidine and asparagine, play only a minor role in human metabolism.