Protein phosphatase enzymes

Although in most instances biological activity results from kinase-mediated phosphorylation of a substrate protein, in some cases dephosphorylation of phosphorylated proteins by phosphatase enzymes are required for signalling purposes. Eight phosphoprotein phosphatase enzymes are currently recognized, classified by whether they remove phosphate groups from phosphoserine/phosphothreonine residues or from phosphotyrosine residues. Protein phosphatase 2B is also referred to as calcineurin. Very recently, an additional molecular device for the feedback regulation of kinase signalling pathways has been described whereby a protein kinase, which is itself regulated by protein phosphorylation, becomes the substrate of a specific protein phosphatase in a self-moderating signalling complex. An example is the interaction between Ca2+-calmodulin-dependent protein kinase IV and protein phosphatase 2A. Ca 2+-calmodulin-dependent protein kinase IV is activated in a calcium-dependent manner involving phosphorylation by the upsteam Ca 2+-calmodulin-dependent protein kinase kinase. Activation is transient and reversible, even in the presence of high levels of intracellular calcium ions, since protein phosphatase 2A binds to the region of Ca 2+-calmodulin-dependent protein kinase IV that encompasses the kinase catalytic domain. This tight regulation of Ca 2+-calmodulin-dependent protein kinase IV phosphorylation by the phosphatase enzyme in a constitutive signalling complex allows rapid adjustment of the signal transmitted by the kinase to achieve an appropriate cellular response.

A further level of regulation is provided by the existence of protein phosphatase inhibitors, such as DARPP-32, found in neurones which express dopamine D 1 receptors. DARPP-32 is a dopamine- and cAMP-regulated phosphoprotein, and by acting as a protein phosphatase inhibitor when it is phosphorylated, can regulate postsynaptic effects of dopamine in dopaminoceptive cells.

Although a variety of cellular proteins are phosphorylated by protein kinases, much attention has been given to phosphorylation of a nuclear protein known as the cAMP/calcium-responsive element binding protein. Phosphorylation of this protein requires translocation of a protein kinase from the cytoplasm to the nuclear membrane. The phosphorylated protein induces gene transcription by binding to a sequence of DNA termed the cAMP binding element. Activation of transcription requires synergism between cAMP/calcium-responsive element binding protein and the calcium-dependent protein phosphatase calcineurin. Thus the cAMP binding element acts as a coincidence detector.

Examples of genes of which transcription is activated once the cAMP binding element site is occupied include the 'immediate-early genes' such as c- fos and c-jun. The products of these genes, known as Fos or Jun proteins, are themselves transcription factors able to regulate the expression of a variety of other genes, including genes for neurotransmitter synthetic enzymes such as tyrosine hydroxylase and for neuropeptides such as dynorphin. In some cases gene transcription is controlled by a dimer of the Fos and Jun proteins, known as the AP-1 transcription factor. Thus the immediate-early genes provide a link between changes at the receptor/second-messenger level at the cell membrane and changes in gene expression in the nucleus, which then provide the basis for long-term adaptations. Induction of immediate-early gene expression always occurs in specific anatomical pathways, and neurotransmitters may have differential effects on the same target gene in different cell types or on different genes in the same cell by inducing distinct patterns of the immediate-early gene products. A corollary of this mechanism is that neurotransmitters can in some situations be thought of as growth factors, even in fully differentiated cells. This growth-factor-like action may be manifested as an ability to maintain the differentiated state of the cell by influencing the transcription of genes characteristic of the cellular phenotype.

Another function served by the phosphorylation reactions is desensitization of receptors. b-Adrenergic receptors, for example, are desensitized following phosphorylation in the cytoplasmic domain of the molecule by cAMP-dependent b-adrenergic receptor kinase, as well s by cAMP-dependent kinases or protein kinase C. Two to three molecules of phosphate are incorporated per receptor molecule, and the degree of desensitization correlates with the degree of phosphorylation. Phosphorylation slows the ability of the receptor to activate G s and also promotes binding of the inhibitory protein arrestin to the phosphorylated receptor.

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