Trends in Cell Biology
PTEN: from pathology to biology
Section snippets
PTEN: a small gene family lacking redundancy
The gene that encodes PTEN is expressed in all eukaryotic cells. The crystal structure of human PTEN shows adjacent phosphatase and C2-domain lobes [7] that is predicted to be preserved in all metazoans. PTEN homologues n Saccharomyces cerevisiae and Schizosaccharomyces pombe fungi have the phosphatase domain, but they lack the C2 domain [8] that is crucial for interaction with the plasma membrane. Although there is only one PTEN gene in fungi and lower metazoans (Caenorhabditis elegans and
Reduced expression of PTEN in tumours
Genetic alteration of both alleles of PTEN occurs in nearly all types of human cancers examined, with the highest frequency of inactivation in glioblastoma and endometrial cancer 12, 13, 14, 15. The typical mechanism of inactivation is mutation accompanied by loss of heterozygosity, the gold standard for gene inactivation. However, in some cases tumours appear to evolve mechanisms to reduce the concentration of PTEN without mutation of the gene [16]. Methylation of the PTEN promoter region,
The PTEN−/− cellular phenotypes
Initial experiments in mice showed that complete loss of PTEN is lethal early in development. Heterozygous mice are viable, however, and adults develop a variety of tumours [1]. Recently, several groups have analysed the effects of conditionally mutating both alleles of PTEN by incorporating lox recombination sites that flank PTEN exons and using tissue-specific promoters to express Cre recombinase. Recombination elicited by Cre led to the mutational inactivation of PTEN. Surprisingly, loss of
Cellular localization of PTEN
Because PTEN regulates PtdIns(3,4,5)P3 at the plasma membrane, some portion of PTEN must reside at this location in the cell. Consistent with this, Das et al. found that a mutant version of PTEN that contains the phosphatase and C2 domains fused with green fluorescent protein (GFP) is expressed at the plasma membrane [31]. Thus, it is surprising that most endogenous PTEN is not found at the plasma membrane. Immunohistochemical studies show that the cellular distribution of PTEN varies between
PTEN and cell migration
It has been shown that PTEN might exert effects on the cytoskeleton and have a role in controlling cell migration. Introducing PTEN into PTEN−/− human tumour cells alters actin fibres and inhibits cell migration [41]. Migration is increased in mouse embryo fibroblasts that lack PTEN. In these cells, elevated PtdIns(3,4,5)P3 leads to activation of Rac1 and Cdc42, both of which are small GTPase mediators of cellular migration [42].
In the past 2 years, several studies in Dictyostelium discoideum
PTEN and PtdIns(3,4,5)P3 targets
Many proteins that containing PH domains bind to PtdIns(3,4,5)P3 with high affinity. In PTEN−/− cells, a large number of different signalling proteins are brought to the plasma membrane by elevated PtdIns(3,4,5)P3 levels. Surprisingly, however, the primary phenotypic output of elevated PtdIns(3,4,5)P3 in metazoans streams through PDK1 to its substrate AKT. Although much experimental data substantiates the importance of the link between PTEN and AKT, perhaps the best evidence is the ability of a
AKT substrates
Many AKT substrates are phosphorylated when PTEN is inactive (Fig. 2) Alterations in the transcription profiles are caused, at least in part, by changes in activity of nuclear factor κB, HIF1-α and forkhead transcription factors 55, 56, 57. Phosphorylation and inhibition of GSK3 (which increases cyclin D and myc levels) 58, 59, and phosphorylation and cytoplasmic sequestration of p27 alters the cell cycle. Apoptosis is inhibited by phosphorylation of caspase 9 and 60, 61. Recent data indicates
S6K and tuberous sclerosis (TSC)
Although the importance of the PDK1–AKT connection is undisputed, other targets of PDK1 such as S6K might also contribute to tumour development. S6K is a regulator of cell size that requires PtdIns(3,4,5)P3, PDK1 and the mammalian target of rapamycin (mTOR) to be activated (Fig. 1). Mammalian cells that lack PTEN have elevated S6K activity [67]. Recently, it has been shown that TSC1 and TSC2 form a complex that inactivates mTOR and so inhibits the activity of S6K [68]. This finding led to
Concluding remarks
The discovery of PTEN represents a milestone in the understanding of tumourigenesis and solves many pieces of a complicated puzzle. But, as always in science, answering one question opens up new ones. In the past few years, many downstream targets of PTEN have been identified and the fundamental role of the PI 3-kinase–PTEN–AKT axis has been further elucidated, but there is still much to be explained. Little is known about the regulation of PTEN transcription and translation, and the half-life,
References (70)
- et al.
PTEN: life as a tumour suppressor
Exp. Cell Res.
(2001) - et al.
PTEN: a tumour suppressor that functions as a phospholipid phosphatase
Trends Cell Biol.
(1999) - et al.
The tumour suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate
J. Biol. Chem.
(1998) Crystal structure of the PTEN tumour suppressor: implications for its phosphoinositide phosphatase activity and membrane association
Cell
(1999)A family of putative tumour suppressors is structurally and functionally conserved in humans and yeast
J. Biol. Chem.
(1997)PTEN 2, a Golgi-associated testis-specific homologue of the PTEN tumour suppressor lipid phosphatase
J. Biol. Chem.
(2001)T cell-specific loss of Pten leads to defects in central and peripheral tolerance
Immunity
(2001)Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways
Cell
(2002)Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways
Dev. Biol.
(2000)Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumours
Am. J. Pathol.
(2000)
Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumours compared to normal islet cells
Am. J. Pathol.
Genetic deletion of the Pten tumour suppressor gene promotes cell motility by activation of Rac1 and Cdc42 GTPases
Curr. Biol.
G protein signaling events are activated at the leading edge of chemotactic cells
Cell
PI 3-kinases and PTEN: how opposites chemoattract
Cell
Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa
Mol. Cell
Spatial and temporal regulation of 3-phosphoinositides by PI 3-kinase and PTEN mediates chemotaxis
Cell
Tumour suppressor PTEN mediates sensing of chemoattractant gradients
Cell
Temporal and spatial regulation of chemotaxis
Dev. Cell
The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway
Mol. Cell
Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
Cell
Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Cell
PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
J. Biol. Chem.
Regulation of PTEN transcription by p53
Mol. Cell
PTEN tumour suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms
Cancer Cell
New insights into tumour suppression: PTEN suppresses tumour formation by restraining the phosphoinositide 3-kinase/AKT pathway
Proc. Natl. Acad. Sci. U. S. A.
p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity
Genes Dev.
A testis-specific gene, TPTE, encodes a putative transmembrane tyrosine phosphatase and maps to the pericentromeric region of human chromosomes 21 and 13, and to chromosomes 15, 22, and Y
Hum. Genet.
TPIP: a novel phosphoinositide 3-phosphatase
Biochem. J.
PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer
Science
PTEN/MMAC1 mutations in endometrial cancers
Cancer Res.
Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies
Cancer Res.
Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers
Nat. Genet.
Inactivation of the tumour suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression
Proc. Natl. Acad. Sci. U. S. A.
Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation
Clin. Cancer Res.
Cited by (292)
Synthetic lethal approaches to target cancers with loss of PTEN function
2023, Genes and DiseasesTherapeutic potential of targeting SHP2 in human developmental disorders and cancers
2020, European Journal of Medicinal ChemistryThe peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5
2018, Molecular and Cellular Endocrinology