Protein regulation phosphorylation

Newton AC (2003) Regulation of the ABC kinases by phosphorylation protein kinase C as a paradigm. Biochem 1370 361-371... 

Mammalian proteins are the targets of a wide range of covalent modification processes. Modifications such as glycosylation, hydroxylation, and fatty acid acylation introduce new structural features into newly synthesized proteins that tend to persist for the lifetime of the protein. Among the covalent modifications that regulate protein function (eg, methylation, adenylylation), the most common by far is phosphorylation-dephos-phorylation. Protein kinases phosphorylate proteins by... 

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

Dl-iike receptors activate the Gs transduction pathway, stimulating the production of adenylyl cyclase, which increases the formation of cyclic adenosine monophosphate (cAMP) and ultimately increases the activity of cAMP-dependent protein kinase (PKA). PKA activates DARPP-32 (dopamine and cyclic adenosine 3, 5 -monophosphate-regulated phosphoprotein, 32 kDa) via phosphorylation, permitting phospho-DARPP-32 to then inhibit protein phosphatase-1 (PP-1). The downstream effect of decreased PP-1 activity is an increase in the phosphorylation states of assorted downstream effector proteins regulating neurotransmitter... 

TABLE 23-3 Examples of proteins regulated by phosphorylation Enzymes involved in neurotransmitter biosynthesis Tyrosine hydroxylase Tryptophan hydroxylase Neurotransmitter receptors Adrenergic receptors Dopamine receptors Opioid receptors Glutamate receptors Many others... 

TABLE 23-3 Examples of proteins regulated by phosphorylation— cont d... 

This list is not intended to be comprehensive but to indicate the wide array of neuronal proteins regulated by phosphorylation. Some of the proteins are specific to neurons but most are present in many cell types in addition to neurons and are included because their multiple functions in the nervous system include the regulation of neuron-specific phenomena. Not included are the many phosphoproteins present in diverse tissues, including brain, that play a role in generalized cellular processes, such as intermediary metabolism, and that do not appear to play a role in neuron-specific phenomena. NMDA, N-methyl-D-aspartate CREB, cAMP response element-binding proteins STAT, signal-transducing activators of transcription ... 

Since then, a plethora of tyrosine-phosphorylated proteins has been discovered. Originally, tyrosine phosphorylation was believed to be involved primarily in regulating cell proliferation, since many oncogene products and growth factor receptors are protein tyrosine kinases (PTKs). However, it has become clear that tyrosine phosphorylation is involved in regulating a variety of cellular processes. In fact, the nervous system contains a large variety of PTKs and protein tyrosine phosphatases (PTPs), and some of these are exclusively expressed in neuronal tissues. Figure 24-1 shows the... 

The phosphorylation of proteins on Ser, Thr or Tyr residues is a basic tool for the regulation of protein activity (see 7.1). Many eucaryotic transcriptional activators are isolated as phosphorylated proteins. The phosphorylation occurrs mainly on the Ser and Thr residues, but can also be observed on the Tyr residues. The extent of phosphorylation is regulated via specific protein kinases and protein phosphatases, each components of signal transduction pathways (see ch. 7). The phosphorylation of transcriptio-... 

Fig. 1.56. Control of eIF-2 by phosphorylation. Phosphorylated eIF-2 GDP binds strongly to eIF-2B without nucleotide exchange occurring. Initiation of protein biosynthesis is not possible in this case.In reticulocytes, eIF-2 is subject to phosphorylation by the heme-regulated eIF-2-kinase (HRI). The activity of the dimeric HRI is regulated via the heme concentration. Another protein kinase that can phosphorylate and regulate eIF-2 is the RNA-dependent eIF2a-kinase (PKR). The latter is induced by interferons and activated by double stranded RNA.

The phosphoprotein-ubiquitin ligases hgate ubiquitin exclusively to phosphorylated proteins. In this system, ubiquitination and degradation are controlled by the phosphorylation status of the target proteins, which is in turn dependent on the regulated activity of protein kinases (or protein phosphatases). Phosphorylation of the target proteins often occurs in sequence elements rich in the aminoacids P,E,S, and T (PEST sequences). For target proteins and the subunit structure, see 13.3.1. 

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