Voltage-Sensing Phosphatase: Its Molecular Relationship With PTEN

Abstract

Voltage-sensing phosphoinositide phosphatase (VSP) contains voltage sensor and cytoplasmic phosphatase domains. A unique feature of this protein is that depolarization-induced motions of the voltage sensor activate PtdIns(3,4,5)P 3 and PtdIns(4,5)P 2 phosphatase activities. VSP exhibits remarkable structural similarities with PTEN, the phosphatase and tensin homolog deleted on chromosome 10. These similarities include the cytoplasmic phosphatase region, the phosphoinositide binding region, and the putative membrane interacting C2 domain. Phosphoinositides and PTENPhosphoinositides constitute up to 4% of the total membrane phospholipids and are located at the inner leaflet of biological membranes. The headgroup of phosphoinositides is composed of an inositol ring with phosphate(s). Phosphoinositides are key second messengers for intracellular signaling, with distinct phosphoinositides having different signaling roles depending on the position and the number of phosphates on the inositol ring. PTEN (phosphatase, tensin homolog, deleted on chromosome TEN) was first identified as a tumor suppressor gene by mapping homozygous deletions on human chromosome 10q23. 3 (23, 24, 45). PTEN exhibits overall homology to protein tyrosine phosphatases and weak homology to tensin, a cell adhesion molecule, and auxilin, a protein involved in synaptic vesicle transport. Because the phosphatase domain of PTEN shows a signature Cysx5-Arg [CX(5)R] motif that is conserved in protein tyrosine phosphatases (PTPs), PTEN was first thought to be a protein phosphatase (24). However, PTEN exhibited only low catalytic activity toward phosphoproteins and peptides. It showed the highest activity toward negatively charged phosphorylated polymers such as Glu-Tyr n , but this activity was low relative to other protein phosphatases (23, 36). PTEN was shown by the Dixon laboratory to dephosphorylate PtdIns(3,4,5)P 3 , making it the first phosphatase identified to utilize a phosphoinositide as its substrate (29,30). A large number of studies with gene knockdown or conditional gene knockout mice have shown that PTEN plays a critical role in diverse biological events, including development, cell growth, cell size, and morphology, through negative regulation of Ptdlns(3,4,5)P 3 .PTEN consists of two major domains (the phosphatase domain and the C2 domain) and three short regulatory regions [the NH 2 -terminal phosphoinositide binding motif (PBM), the COOH-terminal tail region, and the COOH-terminal PDZ binding motif] (see FIGURE 1). The phosphatase domain of PTEN has a similar structure to that of non-metal-regulated phosphatases, including PTPs and dual-specificity phosphatases (22). A study of the crystal structure of PTEN (22) showed that the phosphatase domain has a deeper substrate binding pocket than PTPs and dual-specificity phosphatases, accounting for a much higher preference for phosphoiniositides than protein substrates.The structure of the C2 domain of PTEN is similar to the C2 domain in other proteins, including phospholipase C and phospho...

Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation

“…These enzymes are remarkable in that they hydrolyze phosphoinositides and increase their catalytic activity in response to depolarization. Similar enzymes have been found in other species, notably in Xenopus laevis (1259) and in zebrafish (650) with slightly different voltage characteristics, and the human TPIPs are likely to be their mammalian homologs (1163). The catalytic domains of VSPs are similar to that of PTEN, but they lack the COOH-terminal PEST sequences and the PDZ binding motif.…”

“…The first group contains PTEN (phosphatase and tensin homolog located on chromosome TEN), the voltage-sensitive phosphatases (VSPs) first isolated from the ascidia, Ciona intestinales (1096) but also found in zebrafish (650) and Xenopus (1259), and the mammalian VSP homolgs, the TPIP proteins (␣, ␤ and ␥) (1163). These enzymes all share similar catalytic phosphatase domains (FIGURE 7), but differ in their substrate preference and what phosphates they remove.…”

“…The mammalian TPIP proteins can dephosphorylate 3-phosphorylated inositides (1662), but it is not clear whether they can also act on PtdIns(4,5)P 2 . It is also questionable whether any of the mammalian VSP homologs are also voltage regulated (1163). In spite of the differences in their catalytic targets, these enzymes will be discussed in this section because of their close structural relationship to PTEN, an enzyme that has risen to prominence as a PtdIns(3,4,5)P 3 3-phosphatase and a tumor suppressor gene.…”

Phosphoinositide 5- and 3-phosphatase activities of a voltage-sensing phosphatase in living cells show identical voltage dependence

“…This enzyme domain is homologous to tumor suppressor phosphatase and tensin homolog (PTEN), a phosphoinositide 3-phosphatase that dephosphorylates both phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] (1). Three distinctive regions of PTEN, an N-terminal phospholipidbinding motif that anchors the protein at the plasma membrane, a phosphatase domain that has the enzymatic site, and a C-terminal lipid-interacting C2 domain (9,10), are well conserved in sequence and structure in the VSPs (11)(12)(13)(14).…”

New Experimental Trends for Phosphoinositides Research on Ion Transporter/Channel Regulation

“…The first new technique for PIPs, the voltage-sensing phosphatase (VSP), is composed of a transmembrane voltage sensor and a PI phosphatase (103,104). VSP voltage-dependently dephosphorylates PI(3,4,5)P 3 to PI(3,4)P 2 or PI(3,4)P 2 and PI(4,5)P 2 to phosphatidylinositol 4-phosphate (PI(4)P) (105,106) (Fig.…”