TPIP: a novel phosphoinositide 3-phosphatase

2001 ◽  
Vol 360 (2) ◽  
pp. 277-283 ◽  
Author(s):  
Steven M. WALKER ◽  
C. Peter DOWNES ◽  
Nick R. LESLIE
Keyword(s):  
Endoplasmic Reticulum ◽  
Phosphatase Activity ◽  
Splice Variants ◽  
Critical Role ◽  
Tumour Suppressor ◽  
Metabolizing Enzymes ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor is a phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] 3-phosphatase that plays a critical role in regulating many cellular processes by antagonizing the phosphoinositide 3-kinase signalling pathway. We have identified and characterized two human homologues of PTEN, which differ with respect to their subcellular localization and lipid phosphatase activities. The previously cloned, but uncharacterized, TPTE (transmembrane phosphatase with tensin homology) is localized to the plasma membrane, but lacks detectable phosphoinositide 3-phosphatase activity. TPIP (TPTE and PTEN homologous inositol lipid phosphatase) is a novel phosphatase that occurs in several differentially spliced forms of which two, TPIPα and TPIPβ, appear to be functionally distinct. TPIPα displays similar phosphoinositide 3-phosphatase activity compared with PTEN against PtdIns(3,4,5)P3, PtdIns(3,5)P2, PtdIns(3,4)P2 and PtdIns(3)P, has N-terminal transmembrane domains and appears to be localized on the endoplasmic reticulum. This is unusual as most signalling-lipid-metabolizing enzymes are not integral membrane proteins. TPIPβ, however, lacks detectable phosphatase activity and is cytosolic. TPIP has a wider tissue distribution than the testis-specific TPTE, with specific splice variants being expressed in testis, brain and stomach. TPTE and TPIP do not appear to be functional orthologues of the Golgi-localized and more distantly related murine PTEN2. We suggest that TPIPα plays a role in regulating phosphoinositide signalling on the endoplasmic reticulum, and might also represent a tumour suppressor and functional homologue of PTEN in some tissues.

The regulation of cell migration by PTEN

2005 ◽  
Vol 33 (6) ◽  
pp. 1507-1508 ◽  
Author(s):  
N.R. Leslie ◽  
X. Yang ◽  
C.P. Downes ◽  
C.J. Weijer
Keyword(s):  
Cell Migration ◽  
Phosphatase Activity ◽  
Tumour Suppressor ◽  
Chromosome 10 ◽  
Cellular Processes ◽  
Lipid Phosphatase ◽  
Directed Cell Migration ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

In vertebrates, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) regulates many cellular processes through its PtdIns(3,4,5)P3 lipid phosphatase activity, antagonizing PI3K (phosphoinositide 3-kinase) signalling. Given the important role of PI3Ks in the regulation of directed cell migration and the role of PTEN as an inhibitor of migration, it is somewhat surprising that data now indicate that PTEN is able to regulate cell migration independent of its lipid phosphatase activity. Here, we discuss the role of PTEN in the regulation of cell migration.

scholarly journals Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer

2018 ◽  
Vol 19 (12) ◽  
pp. 3931 ◽  
Author(s):  
Fatemeh Mazloumi Gavgani ◽  
Victoria Smith Arnesen ◽  
Rhîan Jacobsen ◽  
Camilla Krakstad ◽  
Erling Hoivik ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Gene Copy Number ◽  
Biochemical Properties ◽  
Class I ◽  
Gene Copy ◽  
Gene Encoding ◽  
Cellular Processes ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

The phosphoinositide 3-kinase (PI3K) signalling pathway is highly dysregulated in cancer, leading to elevated PI3K signalling and altered cellular processes that contribute to tumour development. The pathway is normally orchestrated by class I PI3K enzymes and negatively regulated by the phosphatase and tensin homologue, PTEN. Endometrial carcinomas harbour frequent alterations in components of the pathway, including changes in gene copy number and mutations, in particular in the oncogene PIK3CA, the gene encoding the PI3K catalytic subunit p110α, and the tumour suppressor PTEN. PIK3CB, encoding the other ubiquitously expressed class I isoform p110β, is less frequently altered but the few mutations identified to date are oncogenic. This isoform has received more research interest in recent years, particularly since PTEN-deficient tumours were found to be reliant on p110β activity to sustain transformation. In this review, we describe the current understanding of the common and distinct biochemical properties of the p110α and p110β isoforms, summarise their mutations and highlight how they are targeted in clinical trials in endometrial cancer.

Substrate specificity and acute regulation of the tumour suppressor phosphatase, PTEN

2007 ◽  
Vol 74 ◽  
pp. 69-80 ◽  
Author(s):  
C. Peter Downes ◽  
Nevin Perera ◽  
Sarah Ross ◽  
Nick R. Leslie
Keyword(s):  
Protein Phosphatase ◽  
Current Model ◽  
Tumour Suppressor ◽  
Protein Substrates ◽  
Dual Specificity ◽  
Survival And Growth ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue ◽  
A Current ◽  
Inhibit Cell Proliferation

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumour suppressor that functions as a PtdIns(3,4,5)P3 3-phosphatase to inhibit cell proliferation, survival and growth by antagonizing PI3K (phosphoinositide 3-kinase)-dependent signalling. Recent work has begun to focus attention on potential biological functions of the protein phosphatase activity of PTEN and on the possibility that some of its functions are phosphatase-independent. We discuss here the structural and regulatory mechanisms that account for the remarkable specificity of PTEN with respect to its PtdIns substrates and how it avoids the soluble headgroups of PtdIns that occur commonly in cells. Secondly we discuss the concept of PTEN as a constitutively active enzyme that is subject to negative regulation both physiologically and pathologically. Thirdly, we review the evidence that PTEN functions as a dual specificity phosphatase with discrete lipid and protein substrates. Lastly we present a current model of how PTEN may participate in the control of cell migration.

The tumour suppressor PTEN mediates a negative regulation of the E3 ubiquitin-protein ligase Nedd4

2008 ◽  
Vol 412 (2) ◽  
pp. 331-338 ◽  
Author(s):  
Younghee Ahn ◽  
Chae Young Hwang ◽  
Seung-Rock Lee ◽  
Ki-Sun Kwon ◽  
Cheolju Lee
Keyword(s):  
Kinase Inhibitor ◽  
Apoptotic Cell ◽  
Tumour Suppressor ◽  
Pcr Analysis ◽  
Multifunctional Protein ◽  
Ubiquitin Protein Ligase ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue ◽  
Nih 3T3 ◽  
Gene 4

The tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10; a phosphatidylinositol 3-phosphatase) is a multifunctional protein deregulated in many types of cancer. It is suggested that a number of proteins that relate with PTEN functionally or physically have not yet been found. In order to search for PTEN-interacting proteins that might be crucial in the regulation of PTEN, we exploited a proteomics-based approach. PTEN-expressing NIH 3T3 cell lysates were used in affinity chromatography and then analysed by LC–ESI–MS/MS (liquid chromatography–electrospray ionization–tandem MS). A total of 93 proteins were identified. Among the proteins identified, we concentrated on the E3 ubiquitin-protein ligase Nedd4 (neural-precursor-cell-expressed, developmentally down-regulated gene 4), and performed subsequent validation experiments using HeLa cells. Nedd4 inhibited PTEN-induced apoptotic cell death and, conversely, the Nedd4 level was down-regulated by PTEN. The down-regulation effect was diminished by a mutation (C124S) in the catalytic site of PTEN. Nedd4 expression was also decreased by a PI3K (phosphoinositide 3-kinase) inhibitor, LY294002, suggesting that the regulation is dependent on the phosphatase-kinase activity of the PTEN-PI3K/Akt pathway. Semi-quantitative real-time PCR analysis revealed that Nedd4 was transcriptionally regulated by PTEN. Thus our results have important implications regarding the roles of PTEN upon the E3 ubquitin ligase Nedd4 as a negative feedback regulator as well as a substrate.

Metabolic switching of PI3K-dependent lipid signals

2007 ◽  
Vol 35 (2) ◽  
pp. 188-192 ◽  
Author(s):  
C.P. Downes ◽  
N.R. Leslie ◽  
I.H. Batty ◽  
J. van der Kaay
Keyword(s):  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Metabolic Switch ◽  
Inositol Phosphatase ◽  
Lipid Phosphatase ◽  
Metabolic Switching ◽  
Pi3k Signalling ◽  
Src Homology ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

The lipid phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10), is the product of a major tumour suppressor gene that antagonizes PI3K (phosphoinositide 3-kinase) signalling by dephosphorylating the 3-position of the inositol ring of PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 is also metabolized by removal of the 5-phosphate catalysed by a distinct family of enzymes exemplified by SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] and SHIP2. Mouse knockout studies, however, suggest that PTEN and SHIP2 have profoundly different biological functions. One important reason for this is likely to be that SHIP2 exists in a relatively inactive state until cells are exposed to growth factors or other stimuli. Hence, regulation of SHIP2 is geared towards stimulus dependent antagonism of PI3K signalling. PTEN, on the other hand, appears to be active in unstimulated cells and functions to maintain basal PtdIns(3,4,5)P3 levels below the critical signalling threshold. We suggest that concomitant inhibition of cysteine-dependent phosphatases, such as PTEN, with activation of SHIP2 functions as a metabolic switch to regulate independently the relative levels of PtdIns(3,4,5)P3 and PtdIns(3,4)P2.

scholarly journals Functional analysis of the protein phosphatase activity of PTEN

2012 ◽  
Vol 444 (3) ◽  
pp. 457-464 ◽  
Author(s):  
Xiaoqun Catherine Zhang ◽  
Antonella Piccini ◽  
Michael P. Myers ◽  
Linda Van Aelst ◽  
Nicholas K. Tonks
Keyword(s):  
Phosphatase Activity ◽  
Protein Phosphatase ◽  
Laser Scanning ◽  
Fluorescent Protein ◽  
Tumour Suppressor ◽  
Laser Scanning Microscopy ◽  
Binding Motif ◽  
Spine Density ◽  
Lipid Phosphatase

In vitro, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) displays intrinsic phosphatase activity towards both protein and lipid substrates. In vivo, the lipid phosphatase activity of PTEN, through which it dephosphorylates the 3 position in the inositol sugar of phosphatidylinositol derivatives, is important for its tumour suppressor function; however, the significance of its protein phosphatase activity remains unclear. Using two-photon laser-scanning microscopy and biolistic gene delivery of GFP (green fluorescent protein)-tagged constructs into organotypic hippocampal slice cultures, we have developed an assay of PTEN function in living tissue. Using this bioassay, we have demonstrated that overexpression of wild-type PTEN led to a decrease in spine density in neurons. Furthermore, it was the protein phosphatase activity, but not the lipid phosphatase activity, of PTEN that was essential for this effect. The ability of PTEN to decrease neuronal spine density depended upon the phosphorylation status of serine and threonine residues in its C-terminal segment and the integrity of the C-terminal PDZ-binding motif. The present study reveals a new aspect of the function of this important tumour suppressor and suggest that, in addition to dephosphorylating the 3 position in phosphatidylinositol phospholipids, the critical protein substrate of PTEN may be PTEN itself.

Inhibiting PTEN

2007 ◽  
Vol 35 (2) ◽  
pp. 257-259 ◽  
Author(s):  
E. Rosivatz
Keyword(s):  
Glucose Uptake ◽  
Drug Target ◽  
Cell Cycle Progression ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Tumour Suppressor ◽  
Key Enzyme ◽  
And Migration ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is well known as a tumour suppressor. In dephosphorylating the 3-position of the inositol ring of phosphoinositides such as PtdIns(3,4,5)P3, PTEN's lipid phosphatase activity is an important counteracting mechanism in PI3K (phosphoinositide 3-kinase) signalling. This is essential for cell motility and migration due to the achievement of a PtdIns(3,4,5)P3/PtdIns(4,5)P2 gradient that is also involved in metastasis. Furthermore, PTEN's tumour suppressor role is linked to the control of cell-cycle progression and cell proliferation by counteracting Akt (also called protein kinase B) signalling which is PtdIns(3,4,5)P3-dependent. Akt is upstream of several kinases involved in proliferation and apoptotic signalling which are often found to be deregulated or mutated in tumours. However, Akt is also the key enzyme in insulin signalling regulating glucose uptake and cell growth. Therefore PTEN has recently moved into the spotlight as a drug target in diabetes. This review summarizes studies undertaken on PTEN's role in glucose uptake, insulin resistance, diabetes and its controversial role in GLUT (glucose transporter)-mediated glucose uptake. Currently available techniques for inhibiting PTEN and the suitability of PTEN as a drug target will be discussed.

scholarly journals A Nanopore Phosphorylation Sensor for Single Oligonucleotides and Peptides

Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Yi-Lun Ying ◽  
Jie Yang ◽  
Fu-Na Meng ◽  
Shuang Li ◽  
Meng-Ying Li ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Single Molecule ◽  
Critical Role ◽  
Label Free ◽  
Peptide Substrates ◽  
Regulatory Pathways ◽  
Single Molecule Level ◽  
Cellular Processes ◽  
One Step ◽  
Targeted Drug Discovery

The phosphorylation of oligonucleotides and peptides plays a critical role in regulating virtually all cellular processes. To fully understand these complex and fundamental regulatory pathways, the cellular phosphorylate changes of both oligonucleotides and peptides should be simultaneously identified and characterized. Here, we demonstrated a single-molecule, high-throughput, label-free, general, and one-step aerolysin nanopore method to comprehensively evaluate the phosphorylation of both oligonucleotide and peptide substrates. By virtue of electrochemically confined effects in aerolysin, our results show that the phosphorylation accelerates the traversing speed of a negatively charged substrate for about hundreds of time while significantly enhances the translocation frequency of a positively charged substrate. Thereby, the kinase/phosphatase activity could be directly measured with the aerolysin nanopore from the characteristically dose-dependent event frequency of the substrates. By using this straightforward approach, a model T4 oligonucleotide kinase (PNK) further achieved the nanopore evaluation of its phosphatase activity and real-time monitoring of its phosphatase-catalyzed dephosphorylation at a single-molecule level. Our study provides a step forward to nanopore enzymology for analyzing the phosphorylation of both oligonucleotides and peptides with significant feasibility in fundamental biochemical researches, clinical diagnosis, and kinase/phosphatase-targeted drug discovery.

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