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.

PI3K/Akt-mediated regulation of p53 in cancer

2014 ◽  
Vol 42 (4) ◽  
pp. 798-803 ◽  
Author(s):  
Aswin G. Abraham ◽  
Eric O’Neill
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cancer Cells ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Negative Control ◽  
Double Minute ◽  
Murine Double Minute ◽  
Phosphoinositide 3 Kinase ◽  
Phosphatase And Tensin Homologue

Mutations activating the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway and inactivating the TP53 tumour-suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. In a well-described mechanism, Akt mediates negative control of p53 levels through enhancing MDM2 (murine double minute 2)-mediated targeting of p53 for degradation. Accumulating evidence is beginning to suggest that, in certain circumstances, PTEN (phosphatase and tensin homologue deleted on chromosome 10)/PI3K/Akt also promotes p53 translation and protein stability, suggesting that additional mechanisms may be involved in the Akt-mediated regulation of p53 in tumours. In the present article, we discuss these aspects in the light of clinical PI3K/Akt inhibitors, where information regarding the effect on p53 activity will be a crucial factor that will undoubtedly influence therapeutic efficacy.

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.

Role of PTEN/PI3K pathway in endothelial cells

2007 ◽  
Vol 35 (2) ◽  
pp. 172-176 ◽  
Author(s):  
A. Suzuki ◽  
K. Hamada ◽  
T. Sasaki ◽  
T.W. Mak ◽  
T. Nakano
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Suppressor Gene ◽  
Pi3k Pathway ◽  
Tumour Suppressor Gene ◽  
Regulatory Subunit ◽  
Heterozygous Mutation ◽  
Homozygous Mutation ◽  
Cowden Disease ◽  
Phosphatase And Tensin Homologue

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is an important tumour-suppressor gene that encodes a 3-phosphatase. The major substrate of PTEN is PIP3 (phosphatidylinositol 3,4,5-trisphosphate) generated by the action of PI3Ks (phosphoinositide 3-kinases). Hereditary mutation of PTEN causes tumour-susceptibility diseases such as Cowden disease. We used the Cre-loxP system to generate an endothelial cell-specific mutation of PTEN in mice. Heterozygous mutation of PTEN in endothelial cells enhances postnatal neovascularization, including tumour angiogenesis necessary for tumour growth. This observation suggests that Cowden disease patients are not only at risk for additional tumorigenic mutations due to complete loss of PTEN function, but may also experience accelerated growth of incipient tumours due to enhanced angiogenesis. Homozygous mutation of Pten in murine endothelial cells impairs cardiovascular morphogenesis and is embryonic lethal due to endothelial cell hyperproliferation and impaired vascular remodelling. Additional homozygous mutation of p85α, the regulatory subunit of class IA PI3Ks, or p110γ, the catalytic subunit of the sole class IB PI3K, led to a partial rescue of all phenotypes in our PTEN-deficient mice. Thus inhibition of the PI3K pathway, including the targeting of PI3Kγ, may be an attractive therapeutic strategy for the treatment of various malignancies.

scholarly journals The role of SHIP1 in T-lymphocyte life and death

2007 ◽  
Vol 35 (2) ◽  
pp. 277-280 ◽  
Author(s):  
G. Gloire ◽  
C. Erneux ◽  
J. Piette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nuclear Factor Κb ◽  
Jurkat Cells ◽  
Critical Pathways ◽  
Inositol Phosphatase ◽  
System Data ◽  
Src Homology ◽  
Phosphoinositide 3 Kinase ◽  
T Cell Lines

SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase-1], an inositol 5-phosphatase expressed in haemopoietic cells, acts by hydrolysing the 5-phosphates from PtdIns(3,4,5)P3 and Ins(1,3,4,5)P4, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathway. SHIP1 plays a major role in inhibiting proliferation of myeloid cells. As a result, SHIP1−/− mice have an increased number of neutrophils and monocytes/macrophages due to enhanced survival and proliferation of their progenitors. Although SHIP1 contributes to PtdIns(3,4,5)P3 metabolism in T-lymphocytes, its exact role in this cell type is much less explored. Jurkat cells have recently emerged as an interesting tool to study SHIP1 function in T-cells because they do not express SHIP1 at the protein level, thereby allowing reintroduction experiments in a relatively easy-to-use system. Data obtained from SHIP1 reintroduction have revealed that SHIP1 not only acts as a negative player in T-cell lines proliferation, but also regulates critical pathways, such as NF-κB (nuclear factor κB) activation, and also appears to remarkably inhibit T-cell apoptosis. On the other hand, experiments using primary T-cells from SHIP1−/− mice have highlighted a new role for SHIP1 in regulatory T-cell development, but also emphasize that this protein is not required for T-cell proliferation. In support of these results, SHIP1−/− mice are lymphopenic, suggesting that SHIP1 function in T-cells differs from its role in the myeloid lineage.

Functional analysis of the tumour suppressor gene PTEN in murine B cells and keratinocytes

2004 ◽  
Vol 32 (2) ◽  
pp. 362-365 ◽  
Author(s):  
A. Suzuki ◽  
T. Sasaki ◽  
T.W. Mak ◽  
T. Nakano
Keyword(s):  
B Cells ◽  
Cytidine Deaminase ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Mutant Mice ◽  
Specific Gene ◽  
Marginal Zone B Cells ◽  
Specific Mutation ◽  
Phosphoinositide 3 Kinase

To investigate the roles of the PTEN (phosphatase and tensin homologue deleted from chromosome 10)/PI3K (phosphoinositide 3-kinase) signalling pathway in vivo, we have generated a series of mutant mice with null or tissue-specific gene-targeted deletions of Pten. Here we present our investigations of Pten function in B cells and keratinocytes in mice. Mice with a B cell-specific mutation of Pten showed increased serum autoantibodies and elevated numbers of B1a cells. Among conventional B (B2) cells in mutant spleens, numbers of marginal zone B cells were significantly increased, while those of follicular B cells were reciprocally decreased. Immunoglobulin class switch recombination was defective and associated with impaired induction of activation-induced cytidine deaminase. Mice with a keratinocyte-specific mutation of Pten exhibited epidermal hyperplasia, hyperkeratosis and accelerated skin morphogenesis. Within 3 weeks of birth, 90% of these animals died of malnutrition, possibly caused by hyperkeratosis of the oesophageal epithelia. Surviving mutant mice developed spontaneous skin tumours within 8.5 months of birth, and chemical treatment accelerated the onset of tumours. Our data show that PTEN is an important regulator in B cells and keratinocytes.

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.

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.

Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells

2011 ◽  
Vol 107 (6) ◽  
pp. 781-790 ◽  
Author(s):  
Barbara Stefanska ◽  
Patrick Salamé ◽  
Andrzej Bednarek ◽  
Krystyna Fabianowska-Majewska
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Vitamin D ◽  
Retinoic Acid ◽  
Breast Cancer Cells ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Phosphatase And Tensin Homologue ◽  
Mcf 7

Aberrations in DNA methylation patterns have been reported to be involved in driving changes in the expression of numerous genes during carcinogenesis and have become promising targets for chemopreventive action of natural compounds. In the present study, we investigated the effects of all-trans retinoic acid (ATRA), vitamin D3 and resveratrol alone and in combination with adenosine analogues, 2-chloro-2′-deoxyadenosine (2CdA) and 9-β-d-arabinosyl-2-fluoroadenine (F-ara-A), on the methylation and expression of phosphatase and tensin homologue (PTEN) tumour suppressor gene in MCF-7 and MDA-MB-231 breast cancer cells. The present results showed that in non-invasive MCF-7 cells, ATRA, vitamin D3 and resveratrol possess high efficacy in the reduction of PTEN promoter methylation. It was associated with PTEN induction as well as DNA methyltransferase down-regulation and p21 up-regulation after treatments with vitamin D3 and resveratrol, suggesting a complex regulation of the DNA methylation machinery. Vitamin D3 and resveratrol improved the inhibitory effects of 2CdA and F-ara-A on PTEN methylation in MCF-7 cells; however, only the combined action of vitamin D3 and 2CdA boosted the induction of PTEN expression, suggesting a cooperation of these compounds in additional processes driving changes in PTEN expression. In contrast, in highly invasive MDA-MB-231 cells, only vitamin D3 reduced PTEN methylation and induced its expression without notable effects in combined treatments. The present results suggest that natural compounds can find application in epigenetic anticancer therapy aimed at inhibition of promoter methylation of tumour suppressor genes and induction of their expression at early stages of carcinogenesis.

scholarly journals Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability

2011 ◽  
Vol 439 (3) ◽  
pp. 391-404 ◽  
Author(s):  
William's Elong Edimo ◽  
Rita Derua ◽  
Veerle Janssens ◽  
Takeshi Nakamura ◽  
Jean-Marie Vanderwinden ◽  
...  
Keyword(s):  
Cell Biology ◽  
Nuclear Speckles ◽  
Akt Phosphorylation ◽  
Inositol Phosphatase ◽  
Signalling Molecules ◽  
Astrocytoma Cells ◽  
Nuclear Lamin ◽  
Src Homology ◽  
Src Homology 2 Domain ◽  
Phosphatase And Tensin Homologue

PtdIns(3,4,5)P3 and PtdIns(3,4)P2 are major signalling molecules in mammalian cell biology. PtdIns(3,4)P2 can be produced by PI3Ks [PI (phosphoinositide) 3-kinases], but also by PI 5-phosphatases including SHIP2 [SH2 (Src homology 2)-domain-containing inositol phosphatase 2]. Proteomic studies in human cells revealed that SHIP2 can be phosphorylated at more than 20 sites, but their individual function is unknown. In a model of PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null astrocytoma cells, lowering SHIP2 expression leads to increased PtdIns(3,4,5)P3 levels and Akt phosphorylation. MS analysis identified SHIP2 phosphosites on Ser132, Thr1254 and Ser1258; phosphotyrosine-containing sites were undetectable. By immunostaining, total SHIP2 concentrated in the perinuclear area and in the nucleus, whereas SHIP2 phosphorylated on Ser132 was in the cytoplasm, the nucleus and nuclear speckles, depending on the cell cycle stage. SHIP2 phosphorylated on Ser132 demonstrated PtdIns(4,5)P2 phosphatase activity. Endogenous phospho-SHIP2 (Ser132) showed an overlap with PtdIns(4,5)P2 staining in nuclear speckles. SHIP2 S132A was less sensitive to C-terminal degradation and more resistant to calpain as compared with wild-type enzyme. We have identified nuclear lamin A/C as a novel SHIP2 interactor. We suggest that the function of SHIP2 is different at the plasma membrane where it recognizes PtdIns(3,4,5)P3, and in the nucleus where it may interact with PtdIns(4,5)P2, particularly in speckles.

Prostate cancer, PI3K, PTEN and prognosis

2017 ◽  
Vol 131 (3) ◽  
pp. 197-210 ◽  
Author(s):  
Helen M. Wise ◽  
Miguel A. Hermida ◽  
Nicholas R. Leslie
Keyword(s):  
Prostate Cancer ◽  
Loss Of Function ◽  
Prostate Cancer Treatment ◽  
Pten Loss ◽  
Genomic Deletions ◽  
Lipid Phosphatase ◽  
Signalling Network ◽  
Prostate Cancer Development ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase

Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress. Here, we discuss these factors and the consequences of PTEN loss, in the context of its role as a lipid phosphatase, as well as current efforts to use available inhibitors of specific components of the PI3K/PTEN/TOR signalling network in prostate cancer treatment.

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