The interconversion of key regulated proteins between phosphorylated and dephosphorylated forms is an extremely versatile and frequently used mechanism for reversibly altering their activities. Many of the phosphorylation-dephosphorylation reactions that take place in vivo appear to be catalysed by relatively few protein kinases and protein phosphatases with pleiotropic actions. Thus cAMP-PK, the CaM-MPK and protein kinase C mediate many of the actions of signals that work through cyclic AMP or Ca2+, or which stimulate PIP2 turnover. Several additional protein kinases are also important in cellular control (e.g. glycogen synthase kinase-3, acetyl CoA carboxylase kinase, tyrosine hydroxylase kinase and casein kinase-2), which are themselves controlled by allosteric effectors, phosphorylation, insulin and other growth factors, or by regulators that have not yet been identified. Four protein phosphatase catalytic units (PP-1, PP-2A, PP-2B and PP-2C) are responsible for dephosphorylating many regulated proteins in the cytoplasm that are phosphorylated on serine and threonine residues. Other protein phosphatases exist, but are either located in mitochondria (Bradford & Yeaman 1986) or dephosphorylate tyrosine residues (Tonks et al. 1987). At least two protein phosphatases (PP-1 and PP-2B) are controlled by second messengers. PP-1 is regulated by cyclic AMP in several ways that vary with form of the enzyme and the tissue. It is inhibited by cyclic AMP through the phosphorylation of inhibitor-1 and its isoforms, through the phosphorylation of targetting proteins such as the glycogen-binding subunit, and through allosteric inhibition by phosphorylase a. The last mentioned mechanism allows PP-1 to be inhibited by Ca2+ in the liver. However, in the cells PP-1 can be activated by Ca2+ through the dephosphorylation of inhibitor-1 by PP-2B. PP-2B is activated by Ca2+ through the interaction of this second messenger with an integral Ca2+-binding subunit, as well as calmodulin itself. These findings demonstrate that protein phosphorylation-dephosphorylation is the basis of a network of interlocking systems that allow hormones and other extracellular signals, acting through just a few second messengers, to coordinate biochemical functions.
|Number of pages||30|
|Journal||Proceedings of the Royal Society B: Biological Sciences|
|Publication status||Published - 22 Jul 1988|