PTEN, here, there, everywhere

Abstract

Loss of function of the phosphatase and tensin homolog (PTEN) tumor suppressor is frequently found in many human malignancies. 1 PTEN antagonizes the phosphatidylinositide 3-kinase (PI3K) pathway 2 by dephosphorylating the 3 0 position of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P 3 ] (or PIP3). 2,3 PIP3 serves as a second messenger whose levels in the plasma membrane are elevated following cell stimulation with growth factors, mediated by the activity of PI3Ks. Proteins containing pleckstrin homology (PH) domains physically interact with PIP3, bringing them into close proximity with other PH domain-containing proteins and facilitating further functional interactions that serve to propagate the membranous signal. 4 PTEN contains an N-terminal phosphatase domain that displays activity not only toward phosphatydilinositol, lipid substrates, but also toward proteinacious ones, although the search for physiologically relevant protein PTEN substrates continues. 5 The C-terminal half of PTEN features a Ca 2 þ -independent C2 domain thought to mediate PTEN interactions with the plasma membrane. 6 A cluster of cationic residues of the b-sandwich, composed of eight b-strands, on the membrane-binding face of PTEN appear to mediate membrane anchoring. 6 Recent evidence suggests further complexity of these interactions, namely, that PTEN SUMOylation at K 266 located within the CBR3 loop has a central role in PTEN membrane association, facilitating the binding of PTEN to the plasma membrane via electrostatic interactions. 7 However, structural analysis using neutron reflectometry challenges this model and demonstrates that the CBR3 loop of PTEN's C2 domain, as well as further electrostatic interactions of the phosphatase domain, is sufficient for membrane association, independent of SUMOylation. 8 PTEN unstructured C terminus, consisting of the last 50 amino acids, has also been implicated in PTEN membrane localization. Guanylate kinase with inverted orientation (MAGI) proteins, which contain PDZ domains, has been shown to bind to the PTEN C-terminal PDZ-domain interaction sequence and reinforce PTEN interaction with the plasma membrane. 9,10 In addition to membrane and cytoplasmic localization, which can be easily associated with its function in regulating the levels of 3 0 phosphorylated phosphatidylinositols, a number of reports, including several recent ones discussed below, point to specific localization of PTEN to other cellular compartments, where it may exert other tumor suppressive functions (Figure 1). For instance, PTEN is readily found in the nuclei of many cultured cells and tissues, including normal breast epithelium, proliferating endometrium, normal pancreatic islet cells, vascular smooth muscle cells, follicular thyroid cells, squamous cell carcinoma and primary cutaneous melanoma. 11 Although nuclear phosphatidylinositols have been reported, they are a part of distinct, partially detergent-resistant proteolipid complexes that are not dynamically regulated and are not likely PTEN substrates. ...

MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor

“…As shown by many studies, PTEN and TP53 are frequently dysregulated in many human malignancies and play a crucial role in the regulation of proliferation and differentiation [ 42 – 44 ]. These studies have shown pro-tumoral effects of p53 inactivation in the stromal fibroblasts, as well as that genetic inactivation of PTEN in CAFs, potentiate both onset and progression of carcinomas [ 42 – 47 ]. It has been reported that BMP2 signaling activate Smad1, in turn inhibits TGF-β-induced PSC activation and ECM formation [ 48 ].…”

PTEN/PTENP1: ‘Regulating the regulator of RTK-dependent PI3K/Akt signalling’, new targets for cancer therapy

“…PTEN is pivotal in the regulation of the receptor tyrosine kinase (RTK) PI-3 kinase (PI3K)/Akt signalling pathway and, as such, even small changes in PTEN expression have been shown to have major consequences for normal cellular function [ 2 – 5 ]. The PTEN protein translocates between the nucleus and the cytoplasm enabling PTEN-specific compartmentalised functions [ 6 , 7 ]. At the molecular level, PTEN expression and cellular abundance is tightly regulated at the transcriptional, post-translational and post-transcriptional levels.…”

Anti-oxidative stress response genes: bioinformatic analysis of their expression and relevance in multiple cancers

“…TXN is a small protein that reduces oxidized proteins and supports peroxiredoxin (PRDX)-mediated H2O2 clearance (Figure 3) [21]. It also positively regulates the activity of PTP1B, the phosphatase of the tyrosine kinase PDGF-beta, leading to increased PDGF-beta signaling [20] and it negatively regulates the tumor suppressor PTEN [22, 23]. These functions point to an oncogenic role of TXN.…”