PTEN: Multiple Functions in Human Malignant Tumors

Abstract

PTEN is the most important negative regulator of the PI3K signaling pathway. In addition to its canonical, PI3K inhibition-dependent functions, PTEN can also function as a tumor suppressor in a PI3K-independent manner. Indeed, the PTEN network regulates a broad spectrum of biological functions, modulating the flow of information from membrane-bound growth factor receptors to nuclear transcription factors, occurring in concert with other tumor suppressors and oncogenic signaling pathways. PTEN acts through its lipid and protein phosphatase activity and other non-enzymatic mechanisms. Studies conducted over the past 10 years have expanded our understanding of the biological role of PTEN, showing that in addition to its ability to regulate proliferation and cell survival, it also plays an intriguing role in regulating genomic stability, cell migration, stem cell self-renewal, and tumor microenvironment. Changes in PTEN protein levels, location, and enzymatic activity through various molecular mechanisms can generate a continuum of functional PTEN levels in inherited syndromes, sporadic cancers, and other diseases. PTEN activity can indeed, be modulated by mutations, epigenetic silencing, transcriptional repression, aberrant protein localization, and post-translational modifications. This review will discuss our current understanding of the biological role of PTEN, how PTEN expression and activity are regulated, and the consequences of PTEN dysregulation in human malignant tumors.

Keywords: PHTS; PI3K; PTEN; cancer; subcellular localization.

Figure 1

Cytoplasmic and nuclear PTEN functions. PTEN acts in regulating a wide spectrum of biological functions, at least in part determined by its subcellular localization. (A) In the cytoplasm PTEN dephosphorylates PIP3 to PIP2, thereby reversing the action of PI3K and hampering all downstream functions controlled by the AKT/mTOR axis, such as cycle progression, induction of cell death, transcription, translation, stimulation of angiogenesis, and stem cell self-renewal. In addition, through its protein phosphatase activity directed against FAK and SHC, PTEN modulates complex pathways affecting cell migration. (B) In the nucleus, PTEN cooperates in maintaining genomic integrity, repairing DNA double-strand breaks, controlling homologous recombination, and promoting ubiquitin-dependent degradation of oncoproteins such as PLK1 and AURK. In addition, PTEN controls cell-cycle progression by modulating ERK phosphorylation and cyclin D1 levels and regulates chromatin remodeling by binding to histone H1.