PTEN

Official Full Name

phosphatase and tensin homolog

Organism

Homo sapiens

GeneID

5728

Background

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. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

Synonyms

BZS; DEC; CWS1; GLM2; MHAM; TEP1; MMAC1; PTEN1; 10q23del; PTENbeta; PTENgama;

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Detailed Information

Phosphatase and tensin homologue deleted on chromosome ten (PTEN) was originally identified as a tumor suppressor gene, which is often lost from a region of chromosome 10q23 in a variety of human tumors, including those of the breast, prostate, and brain. So far, the COSMIC cancer database has listed over 2700 mutations in PTEN in 28 tumor types, and the cBio portal of The Cancer Genome Atlas (TCGA) has listed 1120 mutations in 27 tumor types.

Physiological Role of PTEN

PTEN is a major negative regulator of the signalling pathway defined by class I phosphoinositide 3 kinase (PI3K), the mechanistic target of rapamycin (mTOR) and protein kinase B (AKT) and which plays a key role controlling a wide range of essential cellular processes including cell growth, proliferation, metabolism and survival. The activation of intracellular class I PI3Ks is caused by a variety of cell surface receptors that promote cell growth and proliferation, including many growth factor-activated members of the receptor tyrosine kinases (RTK) cytokine receptors, some integrins and a subset of G-protein coupled receptors which includes several chemokine receptors. These activated receptors directly or indirectly recruit and activate class I PI3K, and then phosphorylate a small fraction of plasma membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to generate phosphatidylinositol-3,4,5-trisphosphate (PIP3), a membrane-associated lipid that acts as a second messenger driving downstream signalling. Increases in local PIP3 levels facilitate the binding of a large number of proteins that carry selective PIP3-binding domains which in turn promote the effects of pathway activation on cell growth, metabolism, proliferation, etc.

More and more evidence shows that PTEN also has significant PIP3-independent functions. Specifically, PTEN protein phosphatase activity is the key to PTEN-mediated inhibition of cellular migration. In glioma cells, it has been shown that the protein phosphatase activity of PTEN is required to induce PTEN phosphorylation and inhibit cellular migration. In addition, there is evidence that PTEN phosphatase activity may regulate glioma cell migration by inhibiting Src family kinases. PTEN also has nuclear functions, which may not be related to its ability to antagonize PI3K signaling. A variety of proteins affect PTEN nuclear localization, thereby affecting the ability of PTEN to act in the nucleus and promote genomic stability. In addition to protein regulation, many studies have shown that PTEN is downregulated by promoter methylation in breast, lung, thyroid, endometrial, gastric, ovarian, and brain tumors. It has also been shown that PTEN is silenced by the expression of many miRNAs and non-coding RNAs. These events are crucial because it has been shown that subtle changes in the dose of PTEN can have profound effects on tumor susceptibility.

Figure 1. PTEN functions in the nucleus and the tumor microenvironment. (Lee Y R, et al., 2018)

PTEN Mutation and Cancer

PTEN was first identified as a tumor suppressor gene on human chromosome 10q23.3, a locus that is highly susceptible to abnormal genetic alterations in primary human cancers, xenografts and cancer cell lines. The PTEN gene has been found to display point mutations in several tumor types, mainly in glioblastoma, endometrial and prostate cancer and to a lesser extent in tumors of the lung, breast and colon. Somatic inactivating PTEN mutations tend to be fairly evenly distributed across its 9 exons, which is a common feature of tumor suppressor genes. However, a large number of mutations are found in the codons encoding arginine residues 130, 173 and 233. A variety of genetic alterations have been identified in the PTEN coding sequence including nonsense, missense and frameshift mutations; splice site variants, deletions and insertions. Many missense mutations are ineffective in function and might serve as a dominant negative to inhibit wild-type PTEN catalytic activity, while many nonsense, missense, and splice site mutations result in unstable truncated proteins that are almost undetectable and therefore are functionally comparable to the PTEN monoallelic loss. Consistent with these multiple possible aberrations, PTEN haploinsufficiency importantly contributes to tumor initiation and progression. Some tumor-derived PTEN mutations retain partial or complete catalytic function, suggesting that alternative mechanisms cause inactivation of PTEN tumor-suppressive function. A compelling example is represented by mutation at Lys289, which alters PTEN subcellular localization.

References:

Álvarez-Garcia V, et al. Mechanisms of PTEN loss in cancer: It's all about diversity. Seminars in Cancer Biology. Academic Press, 2019, 59: 66-79.
Hopkins B D, et al. PTEN function: the long and the short of it. Trends in biochemical sciences, 2014, 39(4): 183-190.
Salmena L. PTEN: History of a tumor suppressor. PTEN. Humana Press, New York, NY, 2016: 3-11.
Lee Y R, et al. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nature reviews Molecular cell biology, 2018, 19(9): 547-562.

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