Protein phosphorylation diseases

The study of protein phosphorylation has helped to clarify the mechanisms involved in the causes and manifestation of disorders of the nervous system. Two illustrative examples are given here Alzheimer s disease and opiate addiction. 

Horrocks, L. A. and Farooqui, A. A. NMDA receptor-stimulated release of arachidonic acid mechanisms for the Bazan effect. In Municio, A. M. and Miras-Portugal, M. T. (eds), Cell Signal Transduction, Second Messengers, and Protein Phosphorylation in Health and Disease. New York Plenum Press, 1994, pp. 113-128. 

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,... 

Cohen, P. (2001) The role of protein phosphorylation in human health and disease the Sir Hans Krebs Medal Lecture. Eur. J. Biochem. 268, 5001-5010. 

Itoh N, Arai H, Urakami K, et al. Large-scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer s disease. Ann Neurol 2001 50(2) 150—156. 

In 1966 Fischer and Krebs published their seminal work on protein phosphorylation and its regulatory function in cellular pathways.1 Since then, great strides have been made in our understanding of protein kinases, their functional roles in cellular processes, and their pathogenic roles in diseases. Bishop and Varmus received the 1989 Nobel Prize for their work on oncogenic kinases.2 In 2001, Nurse and Hunt were also awarded the Nobel Prize for their work in elucidating the role of cyclins and cyclin-dependent kinases in regulating cell cycles.3... 

Moller, H. j., Hampel, H. (2003). Differentiation of geriatric major depression from Alzheimer s disease with CSF tau protein phosphorylated at threonine 231. Am.J. Psychiatry 160, 376-379. 

Davies, P. (2001). Tracking of Alzheimer s disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231. Ann. Neurol. 49, 545-546. 

Tau protein phosphorylated at threonine 181 in csf as a neurochemical taomarker in Alzheimer s disease original data and review of the literamre. J. Mol. Neurosci. 

Keywords Tau Tauopathy Alzheimer s disease Frontotemporal dementia Parkinsonism Exon Microtubule Structural Protein Phosphorylation... 

Wischik CM, Edwards PC, Lai RY, Gertz HN, Xuereb JH, Paykel ES et al (1995) Quantitative analysis of tau protein in paired helical filament preparations implications for the role of tau protein phosphorylation in PHF assembly in Alzheimer s disease. Neurobiol Aging 16 409-417 discussion 418-31... 

As discussed in relation to protein phosphorylation (Ch. 19.3), substoichiometric changes in PTM such as phosphorylation may occru, demanding for a strategy to enable temporal monitoring of differential phosphorylation as a function of (potentially unknown) external or internal stimuli. In fact, some PTM may be disease-related, but others may not. Alternatively, several disease states are related to single amino-acid polymorphism. The state difference may not necessarily be expressed at protein level, but rather in different concentration(s) of small molecules. This is where metabolomics comes into play. 

Protein phosphorylation is arguably one of the most important and ubiquitous events, with 30-60% of all proteins known to exist at one time or other as phosphoproteins. Phosphorylation is a key component of many cellular processes, including proliferation, differentiation, metabolism, signal transduction, and adaptation to environmental stress and in the function of many proteins, hormones, neurotransmitters, and enzymes. An abnormal regulation of phosphorylation often results in disease. Phosphorylation most commonly occurs on serine, threonine, and tyrosine residues whereby the OH group is replaced by a phosphate group, resulting in increase in the mass of those residues by 80 Da. Phosphorylation is a reversible process, mediated by phosphotransferase enzymes, called protein kinases, and are reversed by protein phosphatases. 

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