Phosphatidylinositol phosphatases

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

The rate of production of DAG in the cell does not occur linearly with time, but rather it is biphasic. The first peak is rapid and transient and coincides with the formation of IP3 and the release of Ca2+ this DAG is therefore derived from the PI-PLC catalyzed hydrolysis of phosphatidylinositols [1]. There is then an extended period of enhanced DAG production that is now known to be derived from the more abundant phospholipid phosphatidylcholine (PC), which has a different composition of fatty acid side chains [9]. Although DAG may be generated directly from PC through the action of PC-PLC, it can also be formed indirectly from PC. In this pathway, PC is first hydrolyzed by PLD to give choline and phosphatidic acid, which is then converted to DAG by the action of a phos-phatidic acid phosphatase [10,11 ]. 

Figure 6.9. Pathways of inositol phosphate metabolism. Ins 1,4,5-P3, generated via the hydrolysis of phosphatidyl 4,5-bisphosphate by phospholipase C, can be metabolised by a kinase (to generate Ins 1,3,4,5-P4) or via a phosphatase (to yield Ins 1,4-P2). These products can be metabolised further to produce inositol, which itself may be sequentially phosphory-lated to regenerate phosphatidylinositol 4,5-bisphosphate.

Albumin, tetanus toxin, autocrine motility factor, interleukin-2, alkaline phosphatase, glycosyl-phosphatidylinositol (GPI)-GFP, polyoma virus, and echo virus 1 (26). 

Figure 11.21 Outline of synthesis of phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine and phosphatidylcholine. Note in the synthesis of phosphatidylinositol, the free base, inositol, is used directly. Inositol is produced in the phosphatase reactions that hydrolyse and inactivate the messenger molecule, inositol trisphosphate (IP3). This pathway recycles inositol, so that it is unlikely to be limiting for the formation of phosphatidylinositol bisphosphate (PIP )- This is important since inhibition of recycling is used to treat bipolar disease (mania) (Chapter 12, Figure 12.9). Full details of the pathway are presented in Appendix 11.5. Inositol, along with choline, is classified as a possible vitamin (Table 15.3).

Enzyme Ei is the phospholipase A, for which there is an excess of substrate in the plasma membrane i.e. a zero order process. (Eor details of this process, see Chapter 11). E, is a phosphatase, which catalyses a first order process. In fact, IP2 can be hydrolysed to produce IPi which is further hydrolysed to produce free inositol. The latter is salvaged by using it to re-form phosphatidylinositol in the phospholipid synthetic pathway and then phosphorylated to prodnce PIP2 (Chapter 11, Eigure 11.21). These reactions are not jnst of biochemical interest bnt are involved in the treatment of bipolar disease a mental disorder. 

Figure 12.19 Phosphatidylinositol bisphosphate cycle and treatment of bipolar disease. The metal ion lithium inhibits inositol monophosphate phosphatases and, therefore, inhibits the flux from IP3 to inositol, so that the concentration of the latter decreases. This can restrict formation of phosphatidylinositol the bisphosphate (PIP ) so that the amount in the membrane decreases and the phospholipase no longer catalyses a zero order reaction. The extent of the decrease in the IP3 concentration will depend on how far the process is removed from zero order. This may explain the well-known variability in the response of patients to lithium which is probably dependent on the patient taking the precise dose of the drug (Chapter 14).

Additional information <1, 2, 3, 4, 38> (<2>, in cells loaded with protein-tyrosine phosphatase antibody, phosphatidylinositol 3 -kinase activity is increased by 38%, respectively, compared with control cells loaded with preim-mune IgG [11] <4>, b2-integrins activate the tyrosine kinases p58c-fgr and p59/61hck and causes them to associate with the p85 subunit of Ptdins 3-... 

Blondeau, E Laporte, J. Bodin, S. Superti-Furga, G. Payrastre, B. Man-del, J.-L. Myotubularin, a phosphatase deficient in myotubular myopathy, acts on phosphatidylinositol 3-kinase and phosphatidylinositol 3-phosphate pathway. Hum. Mol. Genet., 9, 2223-2229 (2000)... 

Daniele, N. Rajas, F Payrastre, B. Mauco, G. Zitoun, C. Mithieux, G. Phosphatidylinositol 3-kinase translocates onto liver endoplasmic reticulum and may account for the inhibition of glucose-6-phosphatase during refeeding. J. Biol. Chem., 274, 3597-3601 (1999)... 

Gary, J.D. Sato, T.K. Stefan, C.J. Bonangelino, C.J. Weisman, L.S. Emr, S.D. Regulation of fabl phosphatidylinositol 3-phosphate 5-kinase pathway by vac7 protein and fig4, a polyphosphoinositide phosphatase family member. Mol. Biol. Cell, 13, 1238-1251 (2002)... 

Proteins with long C-terminal hydrophobic signal sequences may become attached to phosphatidylinositol-glycan anchors embedded in the plasma membrane (Fig. 8-13). An example is a human alkaline phosphatase in which the a carboxyl of the terminal aspartate residue forms an amide linkage with the ethanolamine part of the anchor. Attachment may occur by a direct attack of the -NH2 group of the ethanolanine on a peptide linkage in a transacylation reaction that releases a 29-residue peptide from the C terminus.118119 (See Chapter 29). 

Glutamate-mediated Ca2+ entry through NMDA at the plasma membrane level and mobilization of Ca2+from intracellular stores through PLC-mediated generation of PtdIns-3/J is indispensable for the basal NF-kB activity. Three cytosolic Ca2+ sensors, calmodulin, protein kinases C (PKC), and the p2 l(ras)/phosphatidylinositol 3-kinase (Ptdlns-3K)/Akt pathways, are simultaneously involved in the steps linking the Ca2+ to NF-kB activity (Lilienbaum and Israel, 2003 Marchetti et al., 2004 Lubin et al., 2005). Calmodulin modulates calcineurin, a Ca2+-dependent protein phosphatase, which plays a role in the basal NF-kB activity, whilst stimulation of both the calmodulin kinase II and Akt kinase pathways results in the up-regulation of the transcriptional potential of the p65 subunit of NF-/cB (Lilienbaum and Israel,... 

Uncoating requires an interaction with the uncoating ATPase Hsc70. Apparently, however, hydrolysis of phosphatidylinositol (4,5)-bisphosphate is required, which is carried out by the protein synaptojanin. Synaptojanin has two phosphatase domains, and in its absence clathrin-coated vesicles accumulate. Furthermore, the... 

Fig. 2. Targeted lipidomics of 2-AG metabolism. Postulated pathways for 2-AG metabolism. Abbreviations PLC, phospholipase C DAG, diacylglycerol DGL, diacylglycerol lipase MGL, monoacylglycerol lipase PLA, phospholipase A AT, acyltransferase TAGL, triacylglycerol lipase PIP2, phosphatidylinositol bisphosphate ABHD-6/12 hydrolase lyso-PL, lysophospholipid lyso-PA, lysophosphatidic acid PA, phosphatidic add P, phosphatase COX, cydooxygen-ase LOX, lipoxygenase CYP450, cytochrome P450 CDP, cytidine diphosphate.

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