Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTENgene.[6] Mutations of this gene are a step in the development of many
cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (
orthologs)[7] have been identified in most
mammals for which complete genome data are available.
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.[8] It is a target of many anticancer drugs.
PTEN protein acts as a
phosphatase to dephosphorylate
phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN specifically catalyses the
dephosphorylation 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, which plays an important role in regulating cellular behaviors such as cell growth, survival, and migration.
PTEN also has weak protein
phosphatase activity, but this activity is also crucial for its role as a
tumor suppressor. PTEN's protein phosphatase activity may be involved in the regulation of the
cell cycle, preventing cells from growing and dividing too rapidly.[8] There have been numerous reported protein
substrates for PTEN, including
IRS1[10] and
Dishevelled.[11]
Structure
The
structure of the core of PTEN (solved by
X-ray crystallography, see figure to the upper right[5]) reveals that it consists primarily 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 both its phosphatase and C2 domains, bringing the active site to the membrane-bound PIP3 to dephosphorylate it.
The two domains of PTEN, a
protein tyrosine phosphatase domain and a 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,
tensin proteins and
auxilin.[12]
The active site of PTEN consists of three loops, the
TI Loop, the
P Loop, and the
WPD Loop, all named following the
PTPB1 nomenclature.[5] Together they form an unusually deep and wide pocket which allows PTEN to accommodate the bulky
phosphatidylinositol 3,4,5-trisphosphate substrate. The dephosphorylation reaction mechanism of PTEN is thought to proceed through a
phosphoenzyme intermediate, with the formation of a
phosphodiester bond on the active site
cysteine, C124.
Not present in the crystal structure of PTEN is a short 10-amino-acid unstructured region N-terminal of the phosphatase domain (from residues 6 to 15), known variously as the PIP2 Binding Domain (PBD) or PIP2 Binding Motif (PBM)[13][14][15] This region increases PTEN's affinity for the plasma membrane by binding to
Phosphatidylinositol 4,5-bisphosphate, or possibly any anionic lipid.
Also not present in the crystal structure is the
intrinsically disordered C-terminal region (CTR) (spanning residues 353–403). The CTR is constitutively
phosphorylated at various positions that effect various aspects of PTEN, including its ability to bind to lipid membranes, and also act as either a protein or lipid phosphatase.[16][17]
Additionally, PTEN can also be expressed as PTEN-L[18] (known as PTEN-Long, or PTEN-α[19]), a
leucine initiator alternative start site variant, which adds an additional 173 amino acids to the N-terminus of PTEN. The exact role of this 173-amino acid extension is not yet known, either causing PTEN to be secreted from the cell, or to interact with the mitochondria. The N-terminal extension has been predicted to be largely disordered,[20] although there is evidence that there is some structure in the last twenty amino acids of the extension (most proximal to the start
methionine of PTEN).[17]
Clinical significance
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.[21] A number of studies have found increased frequency of PTEN loss in tumours which are more highly visible on diagnostic scans such as
mpMRI, potentially reflecting increased
proliferation and cell density in these tumours.[22]
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.
Non-cancerous neoplasia
Researchers have identified more than 70
mutations in the PTEN gene in people with
Cowden syndrome.[citation needed] These mutations can be changes in a small number of
base pairs or, in some cases, deletions of a large number of base pairs.[citation needed] 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.[23]
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.[23]
Brain function and autism
Defects of the PTEN gene have been cited to be a potential cause of
autism spectrum disorders.[24]
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.[24] People with autism and PTEN mutations may have
macrocephaly (unusually large heads).[25]
Patients with defective PTEN can develop cerebellar mass lesions called dysplastic gangliocytomas or
Lhermitte–Duclos disease.[23]
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[26] been shown to allow nerve regeneration in mice.[27][28]
^Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. (April 1997). "Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers". Nature Genetics. 15 (4): 356–362.
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^
abLi J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. (March 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–1947.
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^Wang X, Shi Y, Wang J, Huang G, Jiang X (September 2008). "Crucial role of the C-terminus of PTEN in antagonizing NEDD4-1-mediated PTEN ubiquitination and degradation". The Biochemical Journal. 414 (2): 221–229.
doi:
10.1042/BJ20080674.
PMID18498243.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. (March 1997). "PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer". Science. 275 (5308): 1943–1947.
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Sansal I, Sellers WR (July 2004). "The biology and clinical relevance of the PTEN tumor suppressor pathway". Journal of Clinical Oncology. 22 (14): 2954–2963.
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Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, et al. (March 2006). "Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse". Nature Medicine. 12 (3): 324–329.
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Dance Your PhD 2017 : A Story of Tumor Suppression Deepti Mathur. PTEN and cancer explained in dance. A metabolic pathway uses glutamine to create a component of DNA. This pathway is regulated in part by PTEN. Loss of PTEN allows the pathway to go into overdrive, leading to cancer. A drug that interrupts the PTEN pathway preferentially destroys cancer cells.
PDBe-KB provides an overview of all the structure information available in the PDB for Human Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN