TNAP, an Essential Player in Membrane Lipid Rafts of Neuronal Cells

Abstract

The tissue non-specific alkaline phosphatase (TNAP) is a glycosyl-phosphatidylinositol (GPI) anchored glycoprotein which exists under different forms and is expressed in different tissues. As the other members of the ecto-phosphatase family, TNAP is targeted to membrane lipid rafts. Such micro domains enriched in particular lipids, are involved in cell sorting, are in close contact with the cellular cytoskeleton and play the role of signaling platform. In addition to its location in functional domains, the extracellular orientation of TNAP and the fact this glycoprotein can be shed from plasma membranes, contribute to its different phosphatase activities by acting as a phosphomonoesterase on various soluble substrates (inorganic pyrophosphate -PPi-, pyridoxal phosphate -PLP-, phosphoethanolamine -PEA-), as an ectonucleotidase on nucleotide-phosphate and presumably as a phosphatase able to dephosphorylate phosphoproteins and phospholipids associated to cells or to extra cellular matrix. More and more data accumulate on an involvement of the brain TNAP both in physiological and pathological situations. This review will summarize what is known and expected from the TNAP localization in lipid rafts with a particular emphasis on the role of a neuronal microenvironment on its potential function in the central nervous system.

Active Probes for Imaging Membrane Dynamics of Live Cells with High Spatial and Temporal Resolution over Extended Time Scales and Areas

“…Figure 1 shows the molecular design of the representative active probe ( 1P ), which consists of three parts: i) cholesterol, a basic component of the cell membrane that not only maintains cell homeostasis and constructs lipid rafts, but also plays crucial roles in cell functions; 12 ii) phosphotyrosine, a substrate of an ectoenzyme (i.e., ubiquitous alkaline phosphatase (ALPL) believed to co-localize with lipid rafts 13 ) that enables an enzymatic reaction on cell surface; iii) 4-nitro-2,1,3-benzoxadiazole (NBD), an environment-sensitive fluorophore that reports molecular self-assembly since this fluorophore exhibits bright fluorescence in hydrophobic environment. 14 Upon the treatment of phosphatase, 1P turns into 1 , which forms fluorescent supramolecular assemblies.…”

Investigation of alpl expression and Tnap-activity in zebrafish implies conserved functions during skeletal and neuronal development

“…Proteolytic shedding processes might lead to cleavage and spreading of active Tnap enzyme within brain compartments and subsequently result in tissue-wide activity. Release of TNAP from the cellular membrane via degradation of its phospholipase mediated GPI-anchor has already been reported and might be one molecular mechanism for this observation 53,54 . Nevertheless, it is unclear to what extent those processes might lead to the observed discrepancy between the different staining methods.…”

(Patho)Physiology of Glycosylphosphatidylinositol-Anchored Proteins I: Localization at Plasma Membranes and Extracellular Compartments

“…In contrast to above, the number of findings about lipolytically cleaved GPI-APs has increased steadily over the past three decades, among them trypanosomal VSG during differentiation of the bloodstream to the procyclic forms of Trypanosoma brucei [176]; human alkaline phosphatase (AP) and ecto-5′-nucleotidase or CD73 upon incubation of human lymphocytes with tumor necrosis factor-α [177], which has been correlated with elevated adenosine levels and extracellular purine metabolism in the blood of adults compared to newborns, fostering an anti-inflammatory immunological status [178,179]; uPAR from breast cancer cells in the extracellular matrix, which has been correlated with neoplastic transformation, tumor growth and mortality [180]; carcinogenic embryonic antigen (CEA) [181]; renal dipeptidase from kidney proximal tubules [182,183]; tissue non-specific alkaline phosphatase (TNAP) [184]; growth arrest specific 1 (GAS1) [185]; and CD14 [186].…”

“…(i) Removal of GPI-APs from the cell surface for degradation and functional inactivation or for activation has been demonstrated for GPI-anchored cell adhesion molecules under the control of PLC2 and PLC6 in Paramecium tetraurelia [196], for brain TNAP in the extracellular neuronal matrix [184], for GAS1 released from neuronal progenitors and glomerular mesangial cells into the cerebrospinal fluid (CSF) and plasma of rats [185] and for CD14 lipolytically released from cultured RAW264 and microglial cells under accompanying downregulation of the signaling induced by peptides, which accumulate in prion, Alzheimer's and Parkinson's diseases [186]. Thus, agents that affect the lipolytic release of certain GPI-anchored (anti)inflammatory signaling molecules in the brain may be envisaged as novel remedies for neurodegenerative diseases.…”