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Enzyme
Compound
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Query: UNIPROT:P43146 (
tumour suppressor
)
5,935
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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)P(3). PtdIns(3,4,5)P(3) 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)P(3) 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)P(3) and PtdIns(3,4)P(2).
...
PMID:Metabolic switching of PI3K-dependent lipid signals. 1737 Dec 35
Reactive oxygen species (ROS) are known to be involved in redox signalling pathways that may contribute to normal cell function as well as disease progression. The
tumour suppressor
PTEN and the inositol 5-phosphatase
SHIP2
are critical enzymes in the control of PtdIns(3,4,5)P(3) level. It has been reported that oxidants, including those produced in cells such as macrophages, can activate downstream signalling via the inactivation of PTEN. The present study evaluates the potential impact of
SHIP2
on phosphoinositides in cells exposed to sodium peroxide. We used a model of
SHIP2
deficient mouse embryonic fibroblasts (MEFs) stimulated by H(2)O(2): at 15 min, PtdIns(3,4,5)P(3) was markedly increased in
SHIP2
-/- cells as compared to +/+ cells. In contrast, no significant increase in PtdIns(3,4)P(2) could be detected at 15 or 120 min incubation of the cells with H(2)O(2) (0.6 mM). PKB activity was also upregulated in
SHIP2
-/- cells as compared to +/+ cells in response to H(2)O(2).
SHIP2
add back experiments in
SHIP2
-/- cells confirm its critical role as a lipid phosphatase in the control of PtdIns(3,4,5)P(3) level in response to H(2)O(2). We conclude that
SHIP2
lipid phosphatase activity plays an important role in the metabolism PtdIns(3,4,5)P(3) which is demonstrated in oxygen stressed cells.
...
PMID:SHIP2 controls PtdIns(3,4,5)P(3) levels and PKB activity in response to oxidative stress. 1764 61
Phosphoinositide signalling molecules interact with a plethora of effector proteins to regulate cell proliferation and survival, vesicular trafficking, metabolism, actin dynamics and many other cellular functions. The generation of specific phosphoinositide species is achieved by the activity of phosphoinositide kinases and phosphatases, which phosphorylate and dephosphorylate, respectively, the inositol headgroup of phosphoinositide molecules. The phosphoinositide phosphatases can be classified as 3-, 4- and 5-phosphatases based on their specificity for dephosphorylating phosphates from specific positions on the inositol head group. The SAC phosphatases show less specificity for the position of the phosphate on the inositol ring. The phosphoinositide phosphatases regulate PI3K/Akt signalling, insulin signalling, endocytosis, vesicle trafficking, cell migration, proliferation and apoptosis. Mouse knockout models of several of the phosphoinositide phosphatases have revealed significant physiological roles for these enzymes, including the regulation of embryonic development, fertility, neurological function, the immune system and insulin sensitivity. Importantly, several phosphoinositide phosphatases have been directly associated with a range of human diseases. Genetic mutations in the 5-phosphatase INPP5E are causative of the ciliopathy syndromes Joubert and MORM, and mutations in the 5-phosphatase OCRL result in Lowe's syndrome and Dent 2 disease. Additionally, polymorphisms in the 5-phosphatase
SHIP2
confer diabetes susceptibility in specific populations, whereas reduced protein expression of SHIP1 is reported in several human leukaemias. The 4-phosphatase, INPP4B, has recently been identified as a
tumour suppressor
in human breast and prostate cancer. Mutations in one SAC phosphatase, SAC3/FIG4, results in the degenerative neuropathy, Charcot-Marie-Tooth disease. Indeed, an understanding of the precise functions of phosphoinositide phosphatases is not only important in the context of normal human physiology, but to reveal the mechanisms by which these enzyme families are implicated in an increasing repertoire of human diseases.
...
PMID:Inositol polyphosphate phosphatases in human disease. 2308 22
SHIP1 is an inositol 5-phosphatase which is well established for its
tumour suppressor
potential in leukaemia. Enzymatically, two SHIP1 substrates, PtdIns(3,4,5)P
3
and Ins(1,3,4,5)P
4
have been identified to date. Additional substrates were found for the homologue
SHIP2
. In this study, we identified new inositol phosphate (InsP) substrates of SHIP1 by metal dye detection high-performance liquid chromatography and compared the substrate profiles of SHIP1 and
SHIP2
. We were able to verify Ins(1,3,4,5)P
4
as a substrate of SHIP1 and interestingly found Ins(1,2,3,4,5)P
5
and Ins(2,3,4,5)P
4
to be preferably used as substrates and Ins(1,4,5,6)P
4
and Ins(2,4,5,6)P
4
to be weak substrates. All of those except Ins(2,3,4,5)P
4
are also known substrates of
SHIP2
indicating a possible exclusive role of Ins(2,3,4,5)P
4
hydrolysis for SHIP1 but not
SHIP2
function.
...
PMID:Characterization of the substrate specificity of the inositol 5-phosphatase SHIP1. 3200 21
The phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is hyperactivated in ~70% of breast cancers. Class I PI3K generates PtdIns(3,4,5)P
3
at the plasma membrane in response to growth factor stimulation, leading to AKT activation to drive cell proliferation, survival and migration. PTEN negatively regulates PI3K/AKT signalling by dephosphorylating PtdIns(3,4,5)P
3
to form PtdIns(4,5)P
2
. PtdIns(3,4,5)P
3
can also be hydrolysed by the inositol polyphosphate 5-phosphatases (5-phosphatases) to produce PtdIns(3,4)P
2
. Interestingly, while PTEN is a bona fide
tumour suppressor
and is frequently mutated/lost in breast cancer, 5-phosphatases such as PIPP,
SHIP2
and SYNJ2, have demonstrated more diverse roles in regulating mammary tumourigenesis. Reduced
PIPP
expression is associated with triple negative breast cancers and reduced relapse-free and overall survival. Although
PIPP
depletion enhances AKT phosphorylation and supports tumour growth, this also inhibits cell migration and metastasis in vivo, in a breast cancer oncogene-driven murine model. Paradoxically,
SHIP2
and SYNJ2 are increased in primary breast tumours, which correlates with invasive disease and reduced survival.
SHIP2
or SYNJ2 overexpression promotes breast tumourigenesis via AKT-dependent and independent mechanisms. This review will discuss how PTEN, PIPP,
SHIP2
and SYNJ2 distinctly regulate multiple functional targets, and the mechanisms by which dysregulation of these distinct phosphoinositide phosphatases differentially affect breast cancer progression.
...
PMID:PTEN and Other PtdIns(3,4,5)P
3
Lipid Phosphatases in Breast Cancer. 3327 99
