Protein kinases overview

Due to the problems in identification of cellular substrates of protein kinases, as described in Chapter 7, it has been a difficult and lengthy process to determine the functionally relevant substrates. Pig. 13.11 gives an overview of the ceU-cycle-specific activation of CDKs and some important substrates. Comparatively sparse information is available on the Gj and S phase substrates of the CDKs. In contrast, many proteins have been described that undergo specific phosphorylation in G2/M phase. The sequence (K/R)-S/T-P-X-K (X any amino acid) has been identified as a consensus sequence for phosphorylation by CDKs. 

Fig. 13.11. Substrates and phase-spedfic activation of CDKs in the ceU cycle. An overview is shown of the phase-specific activation of the most important CDK-cychn complexes and of selected substrates. The arrows indicate activation and phosphorylation. CDK cycMn-dependent protein kinase p53 tumor suppressor p53 pRb tumor suppressor pRb CDC25 CDC25 phosphatase TFIIIB transcription factor TFIIIB R restriction point.

Kappes B, Doerig CD, Graeser R (1999) An overview of Plasmodium protein kinases. Parasitol Today 15(ll) 449-454... 

Vogel et al. (2008) presented a good overview of the mechanisms of action of protein kinase inhibitor. These inhibitors can act by binding directly in the ATP binding site competitively, (type I inhibitors), but they tend to be less specific because of the shared characteristics of the ATP binding pockets among various kinases. More specificity can be attained with type II inhibitors that can extend into an allosteric site next to the ATP pocket and is only available in the inactive (non-phosphorylated) forms of the enzymes. Imatinib is an example of this, with a 200-fold increased... 

The aim of this review is to give the reader a brief overview of the exciting research field of protein kinases. It is, however, by no means a comprehensive overview, and I would like to invite motivated readers to read one of the many excellent reviews on this research topic [4],... 

Mitogen-activated protein kinase (MAPK) cascades were among the first signaling pathways demonstrated to be activated by ROS. These effects have since been extensively investigated. Here, a brief overview on MAPK properties will be followed by a summary of the known physiological roles of MAPK and a paragraph on the mechanisms and consequences of activation of MAPK cascades by ROS. 

Occurrence profiles involving functions, pathways, and other genomic data are used in comparative analysis in a way similar to that previously discussed for genes. For example, occurrence or abundance profiles of certain COGs (such as signal transduction histidine kinase, serine/threonine protein kinase, and phosphatase) can provide a broad overview of protein families present or absent in the genomes of interest, whereas occurrence profiles of Pfam domains found in these proteins could provide additional information on the signals sensed by the proteins. 

After a brief overview of signal transduction, the text describes the structure of the seven-helix transmembrane P-adrenergic receptor and indicates how it transmits to the intracellular side of the plasma membrane a signal arising from binding the hormone epinephrine on the extracellular surface of the cell. The common features of the G proteins are presented next. The description of the information-transmission pathway from hormone stimulus to G proteins to adenylate cyclase is completed by a discussion of how cAMP activates specific protein kinases to modulate the activities of the phosphorylated target proteins. A small number of hormone molecules outside the cell results in an amplified response because each activated enzyme in the triggered cascade forms numerous products. There are many distinct seven-helix transmembrane hormone receptors. 

Figure 21.17 Overview of the regulation of the genes that express three proteins essential for DNA synthesis. The Rb gene expresses Rb which inactivates the transcription factor by forming a complex. Phosphorylation of the Rb protein by a cell cycle kinase causes dissociation of complex and release of transcription factor, which is now active and stimulates expression of the three genes. THFR, tetra hydrofolate reductase. See chapter 20 for details of the actions of cyclins, DNA polymerase and THFR in the cell cycle.

Fig. 9.12. Overview of the Ras signaling pathway. Signals from at least three major signaling pathways meet at the Ras protein. Activation of the Ras protein may be initiated by receptor tyrosine kinases, by G-protein-coupled receptors and by receptors with associated tyrosine kinases. The nature of the communication between the Ras protein and receptors with associated tyrosine kinase or G-protein-coupled receptors is mostly unknown. From the activated Ras protein, the signal is passed to various effector molecules including members of the MEK kinases, PI3-kinase, pl20 GAP and Ral-GEFs. The best understood is the effector function of Raf kinase, which passes a signal to the transcription level via the MAP kinase pathway.

Figure 1 Overview of the different phases of the cell cycle. Quiescent cells are in GO phase and reenter the cell cycle at Gl during which cells prepare for DNA synthesis. After passing the restriction point in late Gl cells are committed to enter S phase, during which DNA replication occurs. Cells in G2 phase prepare for mitosis (M phase). Cell cycle progression is controlled by various positive and negative cell cycle regulatory proteins including cyclins (A, B, D, E) cyclin dependent kinases (cdk 1,2, 4, 6) cdk inhibitors (p15, p16, p18, p19, p21, p27, p57), retinoblastoma (Rb) and p53.

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