Trends in Biochemical Sciences
ReviewThe regulation of protein function by multisite phosphorylation – a 25 year update
Section snippets
Multisite phosphorylation as a ‘docking’ mechanism.
The epidermal growth factor (EGF) receptor is a protein tyrosine kinase that becomes active upon binding to EGF (Ref. 3). This landmark discovery made 20 years ago led to the realization that the receptors for many other growth factors are also tyrosine kinases. However, the search for their physiological substrates was initially ‘disappointing’ in that the major protein that became phosphorylated in response to growth factor stimulation was invariably the receptor itself. Indeed, it was not
Control of degradation and transactivation by multisite phosphorylation.
NF-κB is a transcription factor that plays a key role in the response to cell-damaging agents and infection. It is composed of an inhibitory subunit, IκB, complexed to two other proteins, termed p65 and p50. The phosphorylation of IκB at S32 and S36 by IκB kinase is the signal for the ubiquitination of IκB and its degradation by the 26S proteasome21. The p65–p50 complex can then enter the nucleus to stimulate the transcription of target genes, provided that p65 is itself phosphorylated at S529
Conclusions
The phosphorylation or dephosphorylation of a protein is a flexible mechanism for reversibly altering its conformation and hence its ability to function. However, it is not simply used to switch the activity of a protein on or off, but can have many additional roles. For example, it can affect the rate at which a protein is degraded, its ability to translocate from one subcellular compartment to another, to dock with other proteins or to bind divalent cations. Multisite phosphorylation is a
Acknowledgements
I am indebted to the UK Medical Research Council, The Royal Society of London and Diabetes UK, who have supported my research for many years.
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