|Phosphatase and tensin homolog|
Crystallographic structure of human PTEN. The N-terminal phosphatase domain is colored blue while the C-terminal C2 domain is colored red.
|Symbols||; 10q23del; BZS; CWS1; DEC; GLM2; MHAM; MMAC1; PTEN1; TEP1|
PTEN acts as a tumor suppressor gene through the action of its phosphatase protein product. This phosphatase is involved in the regulation of the cell cycle, preventing cells from growing and dividing too rapidly. It is one of the targets for drug candidates such as the oncomiR, MIRN21.
This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin-like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating Akt/PKB signaling pathway.
Function and structure
The corresponding PTEN protein is found in almost all tissues in the body. PTEN protein acts as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the dephosporylation of the 3` phosphate of the inositol ring in PIP3, resulting in the biphosphate product PIP2 (PtdIns(4,5)P2). This dephosphorylation is important because it results in inhibition of the AKT signaling pathway.
The structure of PTEN (solved by X-ray crystallography, see figure to the upper right) reveals that it consists of a phosphatase domain, and a C2 domain: the phosphatase domain contains the active site, which carries out the enzymatic function of the protein, while the C2 domain binds the phospholipid membrane. Thus PTEN binds the membrane through its C2 domain, bringing the active site to the membrane-bound PIP3 to de-phosphorylate it.
When the PTEN enzyme is functioning properly, it acts as part of a chemical pathway that signals cells to stop dividing and can cause cells to undergo programmed cell death (apoptosis) when necessary. These functions prevent uncontrolled cell growth that can lead to the formation of tumors. There is also evidence that the protein made by the PTEN gene may play a role in cell movement (migration) and adhesion of cells to surrounding tissues.
During tumor development, mutations and deletions of PTEN occur that inactivate its enzymatic activity leading to increased cell proliferation and reduced cell death. Frequent genetic inactivation of PTEN occurs in glioblastoma, endometrial cancer, and prostate cancer; and reduced expression is found in many other tumor types such as lung and breast cancer. Furthermore, PTEN mutation also causes a variety of inherited predispositions to cancer.
Researchers have identified more than 70 mutations in the PTEN gene in people with Cowden syndrome. These mutations can be changes in a small number of base pairs or, in some cases, deletions of a large number of base pairs. Most of these mutations cause the PTEN gene to make a protein that does not function properly or does not work at all. The defective protein is unable to stop cell division or signal abnormal cells to die, which can lead to tumor growth, particularly in the breast, thyroid, or uterus.
Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called hamartomas. These disorders include Bannayan-Riley-Ruvalcaba syndrome and Proteus-like syndrome. Together, the disorders caused by PTEN mutations are called PTEN hamartoma tumor syndromes, or PHTS. Mutations responsible for these syndromes cause the resulting protein to be non-functional or absent. The defective protein allows the cell to divide in an uncontrolled way and prevents damaged cells from dying, which can lead to the growth of tumors.
Brain function and autism
Defects of the PTEN gene have been cited to be a potential cause of autism spectrum disorders. When defective, PTEN protein interacts with the protein of a second gene known as Tp53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus, brain regions critical for social behavior and cognition. When PTEN protein is insufficient, its interaction with p53 triggers deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism.
PTEN's strong link to cell growth inhibition is being studied as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have recently been shown to allow nerve regeneration in mice.
Cell lines with known PTEN mutations include:
- prostate: LNCaP, PC-3
- kidney: 786-O
- glioblastoma: U87MG
- breast : MB-MDA-468, BT549
- bladder: J82, UMUC-3
PTEN (gene) has been shown to interact with:
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- GeneReviews/NCBI/NIH/UW entry on PTEN Hamartoma Tumor Syndrome (PHTS)
- PTEN Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- UMich Orientation of Proteins in Membranes protein/pdbid-1d5r
- "PTEN Gene - phosphatase and tensin homolog". GeneCards. The Weizmann Institute of Science. Retrieved 2009-03-12.
- "Gene overview of all published AD-association studies for PTEN". Alzforum: AlzGene. Alzheimer Research Forum. Retrieved 2009-03-12.
- Research shows gene defect's role in autism-like behavior