Protein tyrosine phosphorylation cellular function

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, with less than 1% on tyrosine (see Ch. 23). 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 [1,2]. 

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

The cellular functions of protein tyrosine phosphatases are closely associated with signal transduction via protein tyrosine kinases. The growth and differentiation promoting signals mediated by protein tyrosine kinases include autophosphorylations and phosphorylation of effector proteins (see 8.1.4). According to current ideas, the activity of protein tyrosine phosphatases may have a negative or positive influence on signal transduction via protein tyrosine kinases. On the one hand, protein tyrosine... 

Our results demonstrated that the identified subsets of the activated protein kinases significantly increased the accuracy of clinical outcome predictions. Most notably in the study, we evaluated protein phosphorylation levels instead of total protein expression levels. Protein phosphorylation and dephosphorylation are well-characterized biochemical processes for protein kinases to conduct cellular signal transduction. Phosphorylation at certain tyrosine, serine, or threonine residues in kinases is a key step for their activation, and the measurement of these phosphorylations reflects their functional status in vivo. Thus, the protein kinase phosphorylation-based tissue microarray more accurately reveals the molecular mechanisms of breast cancers, and more accurately predicts the individualized survival and treatment response. 

Tyrosine kinase receptors These receptors exist in a monomer-dimer equilibrium. The dimer, which is sta-bihzed upon ligand binding, is the signaling structure. Dimer formation stimulates catalytic activity and results in intermolecular autophosphorylation within the dimer and triggers signahng cascades that lead to the phosphorylation of cytoplasmic substrates (insulin receptor as example. Figure 3.1). The increase in phosphorylation of tyrosine residues of intracellular proteins either increases or decreases their activity, particularly that of protein kinases or protein phosphatases that often play a crucial role in the regulation of cellular function. 

Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/ threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates rai-depen-dent and ras-independent intracellular signaling. 

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