Protein phosphorylation and hormone action

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    222 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)115-144
    Number of pages30
    JournalProceedings of the Royal Society B: Biological Sciences
    Volume234
    Issue number1275
    DOIs
    Publication statusPublished - 22 Jul 1988

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