Phospholipid Phosphatases

Phospholipid phosphatases are enzymes such as SHIP (SH2-domain containing inositide-5-phosphatase) or PTEN (phosphatase and tensin homolog deleted on chromosome 10) which dephosphorylate phosphoino-sitides. Whereas SHIP removes phosphate from the 5 ... 

Phosphatases Phospholipid Kinases Phospholipid Phosphatases Protein Phosphatases... 

A selection of other tumor suppressor genes is summarized in Table 14.2. Interestingly, an enzyme of phosphatidyl-inositol metabolism has been also identified as a tumor suppressor. The PTEN tumor suppressor gene codes for a phospholipid phosphatase which specifically cleaves a phosphate from the second messenger phosphatidyl-inosi-tol-3,4,5-trisphosphate (PtdInsPj, see 6.6.2). and thus inactivates the messenger (review Maehama and Dixon, 1999). ... 

Maehama, T. and Dixon, J.E. PTEN a tumour suppressor that functions as a phospholipid phosphatase (1999) Trends Cell Biol 9, 125-128... 

Chia JY, Gajewski JE, Xiao Y et al (2010) Unique biochemical properties of the protein tyrosine phosphatase activity of PTEN-demonstration of different active site structural requirements for phosphopepride and phospholipid phosphatase activities of PTEN. Biochim Biophys Acta 1804 1785-1795... 

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Cellular phosphoinositide concentrations are under tight control by phospholipid kinases and phosphatases. Phospholipid kinases preferentially phosphorylate distinct positions of the inositol ring and hence are subdivided into phosphoinositide 3-kinases (PI3Ks), phosphoinositide 4-kinases (Pl4Ks), and phosphoinositide 5-kinases (PI5Ks) that phosphorylate Pis on position 3, 4 and 5, respectively. In a canonical pathway, Ptdlns... 

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 ]. 

Transfection ofmouse SlPphosphatase into HEK 293 cells, resulting in a 3-fold increase in membrane SIP phosphatase activity, caused a 50% deaease in SIP levels (reduced by 0.6 pmol/nmol phospholipid) and a 2 fold inaease in ceramide (inaeased by 23 pmol/nmol phospholipid) whereas sphingosine levels were similar to vector controls (0.8 pnnol/nmol phosphohpid). SIP phosphatase transfected cells underwent apoptosis in response to serum withdrawal, C2-ceramide, peroxide or doxorubicin with 2-3 fold higher frequency compared to vector-transfected control cells. Surprisingly, exogenously added SIP, which normally confers protechon, inaeased apoptosis. This may be due to its metabolism to ceramide (Mandala et al, 2000) although other factors may also be involved. 

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. 

Zl. Zakim, D., Regulation of microsomal enzymes by phospholipids. I. The effect of phospholipases and phospholipids on glucose 6-phosphatase. J. Biol. Chem. 245, 4953-4961 (1970). 

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