Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling.

Travis J Jerde

doi:10.1155/2015/282567

Abstract

Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP3), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. This review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration.

Highlights

Phosphatase and tensin homolog (PTEN) is a ubiquitously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate t(iPotndIonfs(th3,e4,35󸀠)Pp3hoosrpPhaIPte3)ofbythceaitnaolysziitnolg the ring dephosphorylain PIP3 [1]
The C2 domain is responsible for cellular location and allows PTEN localization to membrane-bound PIP3; this promotes PTEN’s phosphoinositide phosphatase function by locating it to the cellular location of its substrates [2]
PTEN acts as the key endogenous negative modulator of phosphoinositide signaling in mammalian cells, and its role in normal cell homeostasis, proliferation, apoptosis, and many additional components of cell biology is extensive

Summary

Introduction

Phosphatase and tensin homolog (PTEN) is a ubiquitously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol (3,4,5)-trisphosphate t(iPotndIonfs(th3,e4,35󸀠)Pp3hoosrpPhaIPte3)ofbythceaitnaolysziitnolg the ring dephosphorylain PIP3 [1]. Because the downstream signaling pathways that PTEN effects modulate very diverse and dynamic cellular functions, PTEN is responsible for regulating the signals of an abundance of mediators including cytokines, growth factors, integrins, and autacoid ligands of G-protein-coupled receptors [3,4,5]. Interesting recent findings have demonstrated that PTEN modulates the DNA damage response and repair via its inhibition of Akt [18]. Because of this diversity, any mediators that modulate PTEN expression levels or function have substantial effects on cellular function. This review takes a critical look at the literature focusing on PTEN regulation, the effects of this regulation during mammalian development, and how it is regulated by classical developmental signal transduction mechanisms

PTEN in Developmental Biology

PTEN Regulation as Part of Developmental Signaling

Conclusions