PTEN function: the long and the short of it

Abstract

Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a phosphatase that is frequently altered in cancer. PTEN has phosphatase-dependent and -independent roles, and genetic alterations in PTEN lead to deregulation of protein synthesis, the cell cycle, migration, growth, DNA repair, and survival signaling. PTEN localization, stability, conformation, and phosphatase activity are controlled by an array of protein-protein interactions and post-translational modifications. Thus, PTEN-interacting and -modifying proteins have profound effects on the tumor suppressive functions of PTEN. Moreover, recent studies identified mechanisms by which PTEN can exit cells, via either exosomal export or secretion, and act on neighboring cells. This review focuses on modes of PTEN protein regulation and ways in which perturbations in this regulation may lead to disease.

Keywords: PI3K signaling; PTEN; PTEN-Long.

Figure 1

PTEN mutations in cancer. PTEN mutations sites and frequencies were obtained from the cBio Portal of The Cancer Genome Atlas (TCGA). Green dots represent sites for which the majority of alterations are missense mutations. Red dots represent sites for which the majority of alterations are nonsense mutations or frameshifts. Black dots represent sites for which the majoritiy of alterations are in-frame deletions. Purple dots denote sites for which alteration types are mixed [3, 4, 66].

Figure 2

The functions of PTEN. Phosphatase and Tensin Homologue deleted on chromosome ten (PTEN) is a lipid phosphatase that antagonizes phosphatidlynositol 3 kinase (PI3K) signaling by converting phosphatidylinositol (3,4,5) trisphosphate (PIP3) to phosphatidylinositol (4,5) bisphosphate (PIP2). This negatively regulates Protein Kinase B (AKT), Phosphatidylinositol Dependent Kinase-1 (PDK1) and other PIP3-dependent moieties to inhibit growth, protein synthesis, cell cycle progression, metabolism, and migration and allows for apoptosis and cell cycle arrest down stream of receptor tyrosine kinase (RTK) activation at the cell surface. PTEN also acts in a PI3K-independent manner, inhibiting migration and affecting genomic stability, gene expression, and the cell cycle. Functions that are increased by PTEN are in green whereas those inhibited by PTEN are in red. The nucleus is denoted with an ‘N,’ the plasma membrane with a ‘PM,’ and the cytoplasm with a ‘C.’

Figure 3

Post translational modifications of PTEN. PTEN consists of a PIP2-binding domain (PBD), phosphatase domain, C2 domain, tail domain and a PDZ binding domain (PDZbd). Oxidation of PTEN at Cys124 leads to the formation of a disulfide bond with Cys71 (indicated by a broken line) resulting in decreased PTEN activity. PTEN is also acetylated at Lys125 and Lys128 by p300/CREB-binding protein (CBP)-associated factor (PCAF) and at Lys402 by CBP. Ubiquitination of PTEN at Lys13 and Lys 289 by NEDD4-1, X-linked inhibitor of apoptosis (XIAP) and WW domain-containing protein 2 (WWP2) regulates PTEN stability and cellular localization. PTEN SUMOylation at K254 and K266 is critical for PTEN tumor suppressive functions. Dynamic phosphorylation of multiple sites on the C-terminal region of PTEN affects protein stability, phosphatase activity, protein-protein interactions, and cleavage by caspase-3.

Figure 4

PTEN interacting proteins. The binding regions for PTEN-interacting proteins are shown. PTEN-interactors for which the sites of PTEN binding are unknown are listed in the inset box. PTEN-interactors that increase PTEN function are shown in green, and interactors that decrease PTEN function are shown in red.

Figure 5

Trafficking of PTEN-LONG. (A) PTEN-LONG (Green *) is translated and can act in its cell of origin in a manner similar to canonical PTEN. PTEN-Long can act in the nucleus ‘N’, cytoplasm ‘C,’ or at the plasma membrane ‘PM.’ (B) Translation of PTEN-Long (Red *) occurs at the endoplasmic reticulum ‘ER’ and the synthesized protein is transported in the lumen of secretory vesicle. These vesicles then travel to the membrane where they fuse and release PTEN-LONG into the extracellular space. Once outside the cell, PTEN-LONG can interact with extracellular proteins and lipids, as well as with heparinated glycoproteins on the cell surface in order to enter cells. Once inside the cell, PTEN-LONG can act much like canonical PTEN and traffic within the cytoplasm or migrate to the nucleus, therefore increasing the intracellular dose of PTEN in the recipient cell.