Dephosphorylation by protein phosphatases

Phosphorylation by protein kinases of specific seryl, threonyl, or tyrosyl residues—and subsequent dephosphorylation by protein phosphatases—regulates the activity of many human enzymes. The protein kinases and phosphatases that participate in regulatory cascades which respond to hormonal or second messenger signals constimte a bio-organic computer that can process and integrate complex environmental information to produce an appropriate and comprehensive cellular response. 

Phosphorylation of serine, threonine, or tyrosine residues by protein kinases, and their dephosphorylation by protein phosphatases, are critical mechanisms by which information-relaying signals are transduced in eukaryotic cells. Although protein kinases are by no means an eukaryotic invention (see Leonard et al., 1998 for details), the large numbers of protein kinases in eukaryotes (118 in. S . cerevisiae and 435 in C. elegans (Chervitz et al., 1998)) reflect their importance in a multitude of diverse cellular processes. Eukaryotes have evolved signaling pathways that exploit the dual state of an amino acid, dependent on its state of phosphorylation, both as a signaling mechanism and as a means of colocalization of molecules within multimolecular complexes. 

Chowdhury D, Keogh MC, Ishii H, Peterson CL, Buratowski S, Lieberman J (2005) gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA double-strand break repair. Mol Cell 20 801-809. 

Phosphorylation of serine, threonine, and tyrosine side-chain OH groups of proteins by kinases and their dephosphorylation by protein phosphatases provides an important mechanism for biological regulation. Tyrosine phosphatases are not metalloenzymes but the serine/threonine phosphatases contain a bimetallic site. 

Fig. 7.21. Activation of glycogen-bound protein phosphatase I by insulin. Insulin has a stimulating effect on glycogen synthesis by initiating the dephosphorylation and activation of glycogen synthase and the dephosphorylation and inhibition of glycogen phosphorylase. Both enzymes (substrate S in the figure) are dephosphorylated by protein phosphatase PPIG. Insulin mediates the activation of a protein kinase (insulin-sensitive protein kinase) within an insulin-stimulated signal pathway, which phosphorylates and thus activates protein phosphatase PPIG at the PI site.

Gong CX, Grundke-Iqbal 1, Iqbal K (1994b) Dephosphorylation of Alzheimer s disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61 765-772 Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1994c) Alzheimer s disease abnormally phosphorylated tau is dephosphorylated by protein phosphatase-2B (calcineuiin). J Neurochem... 

Figure 3. Model for centrin-G-protein complex assembly in die connecting cilium of photoreceptor cell. Schematic representations of a part of the inner lumen of the photoreceptor connecting cilium. Centrins ( centrin isoforms 1 and 2) (Cen) are physically linked to the inner surface of the microtubule of the connecting cilium(CC). (A) Scenario at high free Ca " concentrations in CC Cen are specifically dephosphorylated by protein phosphatase PP2Cf. Ca "-binding to Cen induces Cen oligomerization and increases affinity of the Gtf -subunit of the visual heterotrimeric G-protein transducin (Gta-GtPy). This may result in trapping G-protein molecules in the connecting cilium and G-protein diffiision is inhibited (Barrier hypothesis, Wolfrum et al. 2002). (B) Scenario at low free Ca " concentrations in CC Cen are specifically phosphorylated by protein kinase CK2. Cen-P decreases affinity of G-protein to Cen. Arrow indicates that free difihision of G-protein is possible, (for references, please see text)...

Turowski P, Myles T, Hemmings BA et al (1999) Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol Biol Cell 10 1997-2015... 

Studies of isomer-specific dephosphorylation by protein phosphatase 2a (PP2a) demonstrated that this enzyme is unable to dephosphorylate the ris-Serp/Thrp-Pro moieties in model peptides [55,56]. A similar specificity was reported for the pro-... 

Figure 2 Covalent modification of glycogen synthase by phosphorylation by different protein kinases and dephosphorylation by protein phosphatase 1.

The dissociation of subunit G from the phosphatase correlates with the phosphorylation of site 2, and not with that of site 1 " and reassociation of G subunit with the phosphatase occurs with dephosphorylation of site 2 by protein phosphatase 2A under conditions where site 1 still retains the phosphate residue as it is more resistant to dephosphorylation by protein phosphatase 2A. Thus, inactivation of the protein phosphatase is due to phosphorylation of site 2 and not site 1. 

Describe the phosphorylation of phosphorylase by phosphorylase kinase and its dephosphorylation by protein phosphatase 1 (PPl). 

When the a subunit is phosphorylated (Section 21.3.2), the (3 subunit is more susceptible to dephosphorylation by protein phosphatase, which causes inactivation. Phosphorylase kinase (and consequently glycogen phosphorylase) therefore would be less active, and the release of glucose from glycogen would be slowed. 

Goedert, M., Cohen, E.S., Jakes, R. and Cohen, P. 1992a. p42 MAP kinase phosphorylation sites in microtubule-assodated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer s disease [corrected]. FEBS Lett. 312 95-99 Goedert, M., Spillantini, M.G., Cairns, N.J. and Crowther, R.A. 1992b. Tau proteins of Alzheimer paired helical filaments abnormal phosphorylation of all six brain isoforms. Neuron 8 159-168... 

Certain serine, tyrosine or threonine residues in proteins can be phosphorylated by protein kinases and dephosphorylated by protein phosphatases (e.g. Chapters 25 and 27). This causes conformational changes in enzyme proteins which increase or decrease activity. This very important regulatory mechanism is confirmed since protein kinases and phosphatases amount to 5% of the proteins encoded by the human genome. Current research has shown that abnormalities of protein phosphoiylation are associated with diseases such as cancer, diabetes and inflammation, the protein kinases and phosphatases are therefore targets for future drug therapy... 

---