Chapter 2:  Cells and within cells

Cells

Translation

Receptor Mechanisms

    Neurons

   Proteins, Protein Structure and Protein Analysis

    Glia

   Epigenetics

   Protein folding in the cell

Within cells

   Transcription

   Post-translational modifications of proteins

   Noncoding RNAs

   Protein degradation in the cell - Autophagy

   Membranes and Membrane Proteins

   miRNAs and the brain

   Protein secretion / Secretory pathway

   The Exctracellular Matrix

Kinases are enzymes which catalyze the phosphorylation of proteins. They do so on hydroxyl groups on the side chains of amino acids within the protein structure. ATP is the phosphate donor in this enzymatic reaction and ADP is generated in the process. The substrate proteins for the kinases are often other enzymes. Phosphorylation of the enzymes affects enzymatic activity.  For some enzymes phosphorylation leads to an activation; for others, it leads to inactivation. By regulating the functioning of enzymes and other proteins in the cell the kinases are very important in regulating cellular events.

There are three amino acids which possess hydroxyl side chain groups required for phosphorylation. These are Serine, Threonine and Tyrosine. The structures of these three amino acids are shown on the left, together with their official three letter codes (Ser, Thr and Tyr) and single letter codes (S, T and Y). Shown in the inserts are the symbolic representation for Ser/Thr and Tyr.

There are two major classes of kinases, those that phosphorylate serine and threonine and those that phosphorylate tyrosine. The former are called Ser/Thr Kinases and the latter are called Tyrosine Kinases. The two classes of kinases differ both with respect to where they are found in a cell and how they are activated. The Ser/Thr kinases are found in the cytoplasm of the cell. They are activated by second messengers (e.g. cyclic AMP, diacylglycerol). These second messengers are generated by enzymes (E) regulated by G proteins (G). The G proteins in turn are activated by receptors (R) for neurotransmitters and neuropeptides. Thus, Ser/Thr kinases are an important element in "G protein coupled receptor signaling". Concerning the tyrosine kinases, there are two types, namely tyrosine kinase receptors and non-receptor tyrosine kinases. This deals with the former type.

Most tryrosine kinases are in fact of the receptor protein type. They are found on the membrane of the cell (see figure) and are directly activated by extracellular messengers. The most common type of ligand for the tyrosine kinase receptors (TKRs) are growth factors such as platelet derived growth factor (PDGF), epidermal growth factor (EGF) and insulin-like growth factors. As well there are a number of brain specific growth factors which function through tyrosine kinase receptors. The receptor for the hormone insulin is also a tryrosine kinase. As mentioned earlier, the kinases (both Ser/Thr and TKRs) phosphorylate intracellular proteins which are often enzymes and thus bring about changes in cell function.

Both Serine/Threonine and Tyrosine kinases possess an ATP-binding site, or domain, and a substrate binding domain. The ATP-binding site holds the ATP in the correct orientation so that one of the high energy phosphate groups (the gamma phosphate group) can be transferred to the hydroxyl group of an amino acid (serine, threonine or tyrosine) within the substrate. In the process ADP is produced which subsequently leaves the kinases. Another ATP is then free bind to the ATP site and the kinase is ready for the next phosphorylation.

Kinases are important in cell signaling 

Protein phosphorylation-dephosphorylation is probably the most crucial chemical reaction taking place in living organisms. It is the basis for the control of many diverse biological events triggered by extracellular effectors such as hormones and neurotransmitters. 

It has been estimated that 30% of intracellular proteins are phosphoproteins and about 4% of the proteins encoded for by the eukaryotic genome are protein kinases and phosphatases. The latter enzymes remove phospho-groups from proteins and are thus also important in the regulation of the protein phosphorylation-dephosphorylation cycle.

Among the kinases, the tyrosine kinases are crucial elements in signal transduction pathways that regulate metabolism, gene expression and cell division. They are of critical importance in the regulation of brain development and differentiation and, in the adult brain are involved in regulating learning and memory processes.