ProteinPhosphorylationHistory

ProteinPhosphorylationHistory - historical perspective The...

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historical perspective NATURE CELL BIOLOGY VOL 4 MAY 2002 http://cellbio.nature.com E127 The origins of protein phosphorylation Philip Cohen The reversible phosphorylation of proteins is central to the regulation of most aspects of cell func- tion but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a per- sonal view of the key findings that have helped to shape the field as we know it today. T he days when protein phosphorylation was an abstruse backwater, best talked about between consenting adults in private, are over. My colleagues no longer cringe on hearing that “phosphorylase kinase phosphorylates phosphorylase” and their eyes no longer glaze over when a “”kinase kinase kinase” is mentioned. This is because protein phosphorylation has gradu- ally become an integral part of all the sys- tems they are studying themselves. Indeed it would be difficult to find anyone today who would disagree with the statement that “the reversible phosphorylation of proteins regu- lates nearly every aspect of cell life”. Phosphorylation and dephosphorylation, catalysed by protein kinases and protein phosphatases, can modify the function of a protein in almost every conceivable way; for example by increasing or decreasing its bio- logical activity, by stabilizing it or marking it for destruction, by facilitating or inhibiting movement between subcellular compart- ments, or by initiating or disrupting pro- tein–protein interactions. The simplicity, flexibility and reversibility of phosphoryla- tion, coupled with the ready availability of ATP as a phosphoryl donor, explains its selection as the most general regulatory device adopted by eukaryotic cells. It is thought that perhaps 30% of the proteins encoded by the human genome contain covalently bound phosphate, and abnormal phosphorylation is now recog- nized as a cause or consequence of many human diseases. A number of naturally occurring toxins and tumour promoters exert their effects by targeting particular protein kinases and phosphatases. A topical example is the cyclic heptapeptide micro- cystin, which has just been listed as a “noti- fiable dangerous substrance”, along with anthrax, in the Anti-terrorism, Crime and Security Act of 2001 recently approved by the British parliament. Microcystin, pro- duced by toxic blue-green algae, is a potent hepatotoxin and liver carcinogen that inhibits members of one of the major fam- ilies of protein phosphatases 1 . In view of these developments, it seems timely to reflect on the early days of research on protein phosphorylation. How was this phenomenon originally discovered as a control mechanism and why did it take so long before its general significance was appreciated? Regulating by phosphorylation
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ProteinPhosphorylationHistory - historical perspective The...

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