PIP3 anchors AKT to the membrane, where AKT is activated through its phosphorylation by phosphoinositide-dependent kinase-1 (PDK1) and mammalian target of rapamycin complex 2 (mTORC2). AKT phosphorylates numerous targets to transduce sig- nals for growth, proliferation, and survival [3]. In addition to its effect on PIP3/AKT pathway, PTEN also regulates p53 function. Mouse double minute 2 homolog (MDM2) is a substrate of AKT, thus acti- vation of AKT on PTEN loss results in MDM2 phosphorylation and increased nuclear import to enhance p53 degradation [4]. PTEN also physically associates with p53 to enhance its DNA binding ability [5]. The domains within PTEN include a phosphatidylinositol-4, 5-bisphosphate–binding

region, a phosphatase domain, a C2 domain, with a C-terminal tail containing two rich in proline, glutamic acid, serine, and threonine (PEST) domains for degradation and a post synaptic density (PDZ) Avasimibe concentration interaction motif (Figure 1A). Mutations of PTEN in GBM include missense, nonsense, frameshift, and splice site mutations distributed throughout the gene, causing disruption Venetoclax of the phosphatase domain by truncation or instability. The most frequently observed mutations in central nervous system (CNS) tumors are amino acid

substitutions at arginine 173 and nonsense mutation at arginine 130. The preferential selection of these “hot spots” suggests that mutants of PTEN may not confer equal oncogenic effects in GBM [6]. The prognostic significance of PTEN in GBM is still a matter of debate. Although multiple clinical studies

have suggested that PTEN mutation in glioma has no correlation with survival or chemosensitivity [7], [8], [9] and [10], some other studies have associated loss of function of PTEN with a more adverse outcome [11], [12] and [13]. Unfortunately, many of these studies lack the sample size or thorough evaluation of PTEN genetic alterations to make concrete conclusions. To precisely evaluate the genuine prognostic significance of PTEN function in brain malig- nancies, comprehensive analysis of GBM at the genetic and expression levels on a large number of morphologically well-defined patients is required [14]. In the present study, we perform a comprehensive analysis on the prognostic value of PTEN status Ergoloid in patients with GBM on the basis of large-scale cancer genomic data. The 586 GBM cases included in this study were well defined in both clinicopathologic and genomic/ proteomic aspects and thus may add an important answer to this controversial field. We also analyze the effects of PTEN mutations on different signaling proteins and experimentally validated the results. By these efforts, we aim to provide mechanistic explanations for the distinct effects of PTEN mutations. The vectors expressing wild-type PTEN were cloned by inserting cDNAs into pcDNA3 vectors through the NheI and XhoI restriction sites.