Lipid 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). 

The great importance of PtdIns(3,4,5)P3 metabolism for growth regulation is illustrated by the observation that an enzyme of PtdIns(3,4,5)P3 metabolism has been identified as a tumor suppressor protein (Wu et al., 1998). PTEN tumor suppressor protein has lipid phosphatase activity that is specific for hydrolysis of PtdIns(3,4,5)P3. It is assumed that PTEN lipid phosphatase is a negative regulator of the Akt pathway by lowering the concentration of PtdIns(3,4,5)P3 and counteracting stimulation of Akt kinase. 

Buj-Bello, A., Laugel, V., Messaddeq, N., Zahreddine, H., Laporte, J., Pellissier, J. F., et al. (2002) The lipid phosphatase myotubu-larin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci USA 99, 15060-15065. Sullivan, T., Escalante-Alcalde, D., Bhatt, H., Anver, M., Bhat, N., Nagashima, K., et al. (1999) Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J Cell Biol 147, 913-920. 

Anandamide was discovered as a high-affinity ligand for CB receptors in 1992 (Devane et al., 1992). Anandamide is produced in response to an increase in intracellular Ca2+ levels or activation of G-protein-coupled receptors (e.g., D2 receptors) (Piomelli, 2003). In mammalian tissues, anandamide is present at concentrations of 1-50 pmol/g (Fig. 4), and can be formed through three distinct biochemical pathways (1) the direct hydrolysis of NAPE by a NAPE-specific phospholipase D (NAPE-PLD) (Okamoto et al., 2005 Wang et al., 2006) (2) the hydrolysis of lyso-NAPE or glycerophospho-anandamide by a specific PLD (Leung et al., 2006 Simon and Cravatt, 2008 Sun et al., 2004) and (3) the hydrolysis of phospho-anandamide by a lipid phosphatase (Liu et al., 2006, 2007) (Fig. 1). 

Clement S, Krause U, Desmedt F, Tanti J.F, Behrends J., Pesesse X., Sasaki T., Penninger J., Doherty M., Malaisse W., Dumont J.E., Le Marchand-Brustel Y., Emeux C., Hue L., and Schurmans S., 2001 The lipid phosphatase SHIP2 controls insulin sensitivity. 

Buj-Bello, A., Laugel, V, Messaddeq, N., Zahreddine, H., Laporte, J., Pellissier, J.F., and Mandel, J.L., 2002, The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but... 

Lipid phosphatase and antagonist of PI3K. Converts the PI3K product phosphoinositol 3,4,5-triphosphate (PIP3) to the PI3K substrate phosphoinositol 4,5-diphosphate (PIP2). 

McDermott Ml, Sigal YJ, Sciorra VA, Morris AJ (2004) Is PRG-1 a new lipid phosphatase Nat Neurosci 7 789 author reply 789-790... 

If SIP is not secreted or dephosphorylated by specific SIP phosphatases, as well as by more general lipid phosphatases, it is cleaved irreversibly to ethanolamine phosphate and rrans-2-hexadecenal by SIP lyase (J. Zhou, 1998 P.P. Van Veldhoven, 20(X)). As shown first in the 1970s by W. Stoffel and coworkers, the phosphoethanolamine can be utilized for the synthesis of phosphatidylethanolamine (Chapter 8), and fran5-2-hexadecenal can be reduced to the alcohol and incorporated into alkyl ether lipids. Under certain conditions, degradation of sphingoid bases can account for as much as one-third of the ethanolamine in phosphatidylethanolamine (E.R. Smith, 1995). It is interesting that both the first enzyme of sphingoid base metabolism (SPT) and the last enzyme, the lyase, are pyridoxal 5 -phosphate-dependent. 

Harris, S.J., Parry, R.V., Westwick, J and Ward, S.G. (2008) Phosphoinositide lipid phosphatases natural regulators of phosphoinositide 3-kinase signaling in T lymphocytes. The Journal of Biological Chemistry, 283, 2465-2469. 

Wain, C.M., Westwick, J., and Ward, S.G. (2005) Heterologous regulation of chemoldne receptor signaling by the lipid phosphatase SHIP in lymphocytes. Cellular SgnaUir 17, 1194-1202. 

Aleem E et al (2005) Cdc2-cyclin E complexes regulate the Gl/S phase transition. Nat Cell Biol 7 831-836 Alexandropoulos K et al (1995) Proline-rich sequences that bind to Src homology 3 domains with individual specificities. Proc Natl Acad Sci USA 92 3110-3114 Ali lU etal (1999) Mutational spectraof PTEN/MMACl gene a tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst 91 1922-1932... 

Clement, S, Krause, U, Desmedt, F, Tanti, JF, Behrends, J, Pesesse, X, Sasaki, T, Penninger, J, Doherty, M, Malaisse, W, Dumont, JE, Le Marchand-Brustel, Y, Emeux, C, Hue, L and Schurmans, S (2001) The lipid phosphatase SHIP2 controls insulin sensitivity. Nature, 409, 92-97. 

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