PTEN (gene)



Phosphatase and tensin homolog (PTEN) is a is_associated_with::protein that, in humans, is encoded by the PTEN is_associated_with::gene. Mutations of this gene are a step in the development of many is_associated_with::cancers. PTEN is_associated_with::orthologs have been identified in most is_associated_with::mammals for which complete genome data are available.

This gene was identified as a is_associated_with::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 is_associated_with::protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates is_associated_with::phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating is_associated_with::Akt/PKB signaling pathway.

Function
The PTEN protein is widely expressed throughout the body. PTEN protein acts as a is_associated_with::phosphatase to dephosphorylate is_associated_with::phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the dephosporylation of the 3` phosphate of the is_associated_with::inositol ring in PIP3, resulting in the biphosphate product PIP2 (is_associated_with::PtdIns(4,5)P2). This dephosphorylation is important because it results in inhibition of the is_associated_with::AKT signaling pathway.

PTEN acts as a is_associated_with::tumor suppressor gene through the action of its is_associated_with::phosphatase protein product. This phosphatase is involved in the regulation of the is_associated_with::cell cycle, preventing cells from growing and dividing too rapidly. It is one of the targets for drug candidates such as the oncomiR, is_associated_with::MIRN21.

Structure
The structure of PTEN (solved by is_associated_with::X-ray crystallography, see figure to the upper right ) reveals that it consists of a is_associated_with::phosphatase domain, and a is_associated_with::C2 domain: the phosphatase domain contains the is_associated_with::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.

The two domains of PTEN, a is_associated_with::protein tyrosine phosphatase domain and a is_associated_with::C2 domain, are inherited together as a single unit and thus constitute a superdomain, not only in PTEN but also in various other proteins in fungi, plants and animals, for example, is_associated_with::tensin proteins and is_associated_with::auxilin.

Cancer
PTEN is one of the most commonly lost tumor suppressors in human cancer; in fact, up to 70% of men with prostate cancer are estimated to have lost a copy of the PTEN gene at the time of diagnosis.

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 is_associated_with::glioblastoma, is_associated_with::endometrial cancer, and is_associated_with::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.

Non-cancerous neoplasia
Researchers have identified more than 70 is_associated_with::mutations in the PTEN gene in people with is_associated_with::Cowden syndrome. These mutations can be changes in a small number of is_associated_with::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 is_associated_with::breast, is_associated_with::thyroid, or is_associated_with::uterus.

Mutations in the PTEN gene cause several other disorders that, like Cowden syndrome, are characterized by the development of non-cancerous tumors called is_associated_with::hamartomas. These disorders include is_associated_with::Bannayan-Riley-Ruvalcaba syndrome and is_associated_with::Proteus-like syndrome. Together, the disorders caused by PTEN mutations are called is_associated_with::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 is_associated_with::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 is_associated_with::p53 triggers deficiencies and defects in other proteins that also have been found in patients with is_associated_with::learning disabilities including is_associated_with::autism.

Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or is_associated_with::Lhermitte–Duclos disease.

Cell regeneration
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
Cell lines with known PTEN mutations include:
 * prostate: is_associated_with::LNCaP, is_associated_with::PC-3
 * kidney: is_associated_with::786-O
 * glioblastoma: is_associated_with::U87MG
 * breast : MB-MDA-468, BT549
 * bladder: J82, UMUC-3

Interactions
PTEN (gene) has been shown to interact with:


 * is_associated_with::CSNK2A2,
 * CSNK2A1,
 * is_associated_with::MAGI3
 * MVP,
 * is_associated_with::NEDD4,
 * NR3C4,
 * is_associated_with::P53, and
 * is_associated_with::PTK2.