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Review
. 2020 Apr 1;10(4):a036087.
doi: 10.1101/cshperspect.a036087.

PTEN in Hereditary and Sporadic Cancer

Joanne Ngeow  1   2   3 , Charis Eng  3   4   5   6
Affiliations
Review

PTEN in Hereditary and Sporadic Cancer

Joanne Ngeow et al. Cold Spring Harb Perspect Med. .

Abstract

Germline pathogenic phosphatase and tensin homolog (PTEN) mutations cause PTEN hamartoma tumor syndrome (PHTS), characterized by various benign and malignant tumors of the thyroid, breast, endometrium, and other organs. Patients with PHTS may present with other clinical features such as macrocephaly, intestinal polyposis, cognitive changes, and pathognomonic skin changes. Clinically, deregulation of PTEN function is implicated in other human diseases in addition to many types of human cancer. PTEN is an important phosphatase that counteracts one of the most critical cancer pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathways. Although PTEN can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. It is positively and negatively regulated at the transcriptional level as well as posttranslationally by phosphorylation, ubiquitylation, oxidation, and acetylation. Although most of its tumor-suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. In this review, we highlight our current knowledge of PTEN function and recent discoveries in understanding PTEN function regulation and how this can be exploited therapeutically for cancer treatment.

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Figures

Figure 1.
Figure 1.
Cytoplasmic and nuclear PTEN signaling. In the cytoplasm, PTEN canonically functions to regulate the phosphatidylinositol 3-phosphate kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Under growth factor stimulation, PI3K is activated and catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 recruits PDK1 to the plasma membrane, which then contributes to the activation of AKT. AKT regulates a myriad of downstream cellular processes such as cell growth, proliferation, and decreased apoptosis. The lipid phosphatase activity of PTEN counteracts PI3K by dephosphorylating PIP3 to PIP2, thereby dampening AKT activation. In the nucleus, PTEN plays a vital role in maintaining genomic stability, chromosomal architecture, cell-cycle control, and the regulation of ribosome biogenesis within nucleoli.
Figure 2.
Figure 2.
PTEN structure and gene mutation spectrum in PTEN hamartoma tumor syndrome (PHTS). (A) Three-dimensional structure of the PTEN protein. PTEN is a 403-amino acid (aa) protein that comprises a amino-terminal region including a phosphatidylinositol 4,5-bisphosphate (PIP2)-binding domain (PBD) and a phosphatase domain, and a carboxy-terminal region including a C2 domain and a PDZ-binding domain. The active site is included between amino acid residues 123 and 130. The carboxy (C) tail contributes to PTEN stability and activity. The PDZ domain is important for protein–protein interactions that play a vital role in cellular signaling transduction. WPD loop, residues 88–98; P loop, residues 123–131; T1 loop, residues 160–171; CBR3 loop, residues 260–269; domain linker, residues 185–191. (B) PTEN germline mutation spectrum from 291 PHTS probands. PTEN consists of nine exons that encode a 403 amino acid protein. Different types of mutations are depicted in the lollipop plot overlaying the PTEN protein structure. The frequency of mutations correlates with the heights of the vertical lines representing each lollipop. The different types of mutations are color-coded as depicted in the key at the top of the figure. (From Yehia et al. 2019, with permission, from Elsevier © 2017.)
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