Role of post-translational regulation pten activity in cancer cell addiction to heterozygous mutations

Alexey Goltsov*, Yusuf Deeni, Hilal Khalil, Michael Idowu, Stylianos Kyriakidis, Gregory Goltsov, Simon P. Langdon, David J. Harrison, James Bown

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Citation (Scopus)

Abstract

PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a key regulator of the PI3K/AKT/mTOR pathway, one of the downstream pathways activated by different intracellular mediators which control cell proliferation, differentiation, motility, survival, and metabolism. PTEN along with phosphoinositide 3-kinase makes up a regulatory hub which strictly controls the pool of the second lipid messenger, PtdIns(3,4,5)P3, an activator of the AKT/mTOR pathway. A genomic analysis of breast and other cancers revealed that this regulatory hub is vulnerable to cancer-driving mutations causing a constant activation of AKT signal. It was established that PTEN is a haploinsufficient tumor suppressor gene with one functional allele being insufficient to maintain wild-type function of PTEN which leads to cancer initiation in mice and humans. The observed PTEN dose-dependence of cancer susceptibility strongly indicates that PTEN is under strict control at both translational and post-translational levels. Haploinsufficiency at the PTEN gene is suggested to synergistically interact with post- translation inactivation of PTEN. More than 15 proteins regulate/inhibit PTEN activity through phosphorylation, ubiquitination, and acetylation via more than 15 PTEN regulatory sites. PTEN-modifier proteins form a PTEN regulatory network connecting the PI3K/AKT/mTOR pathway with multiple pathways relevant to cancer development. Heterozygous PTEN mutations were observed to cooperatively interact with genetic aberrations events in this regulatory network providing selective benefits in cancer progression. The PTEN regulatory network has been revealed to be a druggable target in cancer personalized therapy through restoration of PTEN activity in PTEN-deficient cancers.

Original languageEnglish
Title of host publicationPTEN
Subtitle of host publicationstructure, mechanisms-of-action, role in cell signaling and regulation
EditorsKe Xu
PublisherNova Science Publishers Inc
Pages173-210
Number of pages38
ISBN (Print)9781628080490, 1628080493
Publication statusPublished - 31 Oct 2013

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