Protein phosphorylation (PTP) on tyrosine residues is essential for normal cell signaling, and has a pivotal role in all aspects of cell biology. PTP knockout models in the mouse have led to important breakthroughs in our understanding of the role of PTPs in vivo. However, often redundancy among PTPs obscures elucidation of PTP function. Many PTPs are involved in cell adhesion, which may be reflected by defects in cell migration. This chapter concerns the zebrafish model and investigates the function of PTPs in vertebrates in vivo. It reviews the advantages of the zebrafish as a model system, the conservation of the PTP family in zebrafish, and the initial work that is done to assess the function of PTPs in zebrafish. The study indicates the new directions of PTP research in zebrafish and shows how this will affect analysis of PTP function in higher vertebrates. The zebrafish is being developed as a model system for intravital imaging because of its unique properties, including rapid development and transparency of the embryos.

Protein phosphorylation has become a central focus of drug discovery as the result of the identification and validation of promising therapeutic targets such as protein kinases, protein phosphatases, and phosphoprotein binding domains. With respect to such protein phosphorylation therapeutic targets, significant progress has been made in mapping the signal transduction pathways involved in disease, including in particular the molecular genesis and/or sustainment of various cancers, and several inflammatory, immune, metabolic, and bone diseases. Protein phosphorylation is an extraordinarily important component of life processes, including various signal transduction pathways underlying cellular proliferation, differentiation, metabolism, survival, motility, and gene transcription. Protein phosphorylation is a complex phenomenon, with molecular triggering, compensatory mechanisms, and both spatial and temporal factors contributing to the biological specificity and functional endpoints within the cellular milieu. The global phosphorylation state of proteins in cells is fundamentally impossible to decipher at high resolution, even though sophisticated methods (e.g., mass spectrometry, functional interaction traps, affinity chromatography) are emerging that can be used to analyze the so-called phosphoproteome. In this chapter, protein phosphorylation is described relative to our current understanding of the biology of protein kinase, protein phosphatase, and the phosphoprotein-interacting domain containing intracellular proteins. In addition a few noteworthy examples of drug discovery focused on developing small-molecule inhibitors of such therapeutic targets are described.

Tyrosine Phosphorylation in the Nervous System:

Protein phosphorylation is one of the most important mechanisms in the regulation of cellular function. Proteins can be phosphorylated on serine, threonine or tyrosine residues. Most phosphorylation occurs on serine and threonine (see Ch. 25), with less than 1% on tyrosine. This perhaps accounts for the late discovery of tyrosine phosphorylation, which was found first on polyoma virus middle T antigen in 1979 by Hunter and colleagues (Hunter & Eckhart, 2004). Since then, a plethora of tyrosine-phosphorylated proteins has been discovered. Originally, tyrosine phosphorylation was believed to be involved primarily in regulating cell proliferation, since many oncogene products and growth factor receptors are protein tyrosine kinases (PTKs). However, it has become clear that tyrosine phosphorylation is involved in regulating a variety of cellular processes. In fact, the nervous system contains a large variety of PTKs and protein tyrosine phosphatases (PTPs), and some of these are exclusively expressed in neuronal tissues. The immunocytochemical staining of a cultured hippocampal neuron with a phosphotyrosine antibody (Lau & Huganir, 1995). It reveals the presence of tyrosine-phosphorylated proteins in the cell body as well as in synapses, suggesting that tyrosine phosphorylation may play a role in neuronal function. Furthermore, many neuronal processes are modulated by inhibitors of PTK or PTP, or by modification of the genes encoding these enzymes.

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