From man to mouse and back again: advances in defining tumor AKTivities in vivo

Abstract

AKT hyperactivation is a common event in human cancers, and inhibition of oncogenic AKT activation is a major goal of drug discovery programs. Mouse tumor models that replicate AKT activation typical of human cancers provide a powerful means by which to investigate mechanisms of oncogenic signaling, identify potential therapeutic targets and determine treatment regimes with maximal therapeutic efficacy. This Perspective highlights recent advances using in vivo studies that reveal how AKT signaling supports tumor formation, cooperates with other mutations to promote tumor progression and facilitates tumor-cell dissemination, focusing on well-characterized prostate carcinoma mouse models that are highly sensitive to AKT activation. The implications of these findings on the therapeutic targeting of AKT and potential new drug targets are also explored. Disease Models & Mechanisms DMMPK) (Feng et al., 2004) stimulates full AKT activity. Full activation of AKT leads to additional substrate-specific phosphorylation events, including inhibitory phosphorylation of the proapoptotic FOXO proteins. Dephosphorylation of Ser473 by the PH-domain leucinerich repeat-containing protein phosphatases PHLPP1 and PHLPP2, and the conversion of PtdIns(3,4,5)P 3 to PtdIns(3,4)P 2 by PTEN, inhibits AKT signaling.Human tumors commonly display amplification or overexpression of cell-surface receptors or signaling molecules that activate the PI3K-PTEN-AKT pathway, activating mutations of PI3K, loss of expression of the negative regulator PTEN and/or mutation of AKT (Fig. 1). These mutations account for findings that the AKT pathway is activated in a high proportion of tumors, in a wide variety of tissues; a selection of these findings are summarized in Table 1. From man to mouse: elucidating oncogenic AKT signaling in miceMouse models are invaluable tools for understanding how mutations in PI3K-PTEN-AKT signaling contribute to tumorigenesis in human cancer. In humans, mild mutations in PTEN, TSC1 or TSC2 result in familial tumor-susceptibility syndromes, and a similar neoplasia is seen when the mild mutations are modeled in mice. By contrast, human biopsies of spontaneous tumors that display PTEN, TSC1 or TSC2 loss have increased AKT signaling compared with biopsies of tumors from patients with familial syndromes. This increased AKT signaling and the corresponding more severe tumor development are reflected in mouse models that have heterozygous and homozygous loss of PTEN, TSC1 or TSC2. These studies highlight the contribution that mouse models of AKT activation can make in elucidating oncogenic AKT signaling in familial and spontaneous neoplasia. Human tumor-susceptibility syndromes and neoplasia phenotypes in miceIn humans, mutations in PTEN (which is upstream of AKT), or in TSC1 or TSC2 (which are downstream of AKT), result in complex disease syndromes such as Cowden disease or tuberous sclerosis (Table 2). These diseases display a variety of symptoms (for reviews, see Eng, 2003;Zhou et al., 2003;Crino et al., 2006), because various poi...

PTEN Protein Phosphatase Activity Correlates with Control of Gene Expression and Invasion, a Tumor-Suppressing Phenotype, But Not with AKT Activity

“…These data indicate that AKT activity is necessary for tumour formation in many tissues, and are consistent with the hypothesis that the elevated AKT activity driven by PTEN loss promotes tumour formation. Accordingly, cancer drug discovery programmes to develop AKT inhibitors are well progressed and show some promise (39,40). However, the importance in tumours, and their dependence on, the other additional signalling pathways activated downstream of PTEN and PI3K is poorly understood.…”

Activation of Akt/mTOR Pathway Is Associated with Poor Prognosis of Nasopharyngeal Carcinoma

“…Consecutively, phosphorylation of mTOR regulates two downstream effectors named p70S6K (p70 ribosomal protein S6 kinase) and 4E-BP1 (eukaryotic initiation factor 4E-binding protein1) [4]–[5]. The eIF4E is released to initiate translation after 4E-BP1 phosphorylation, while p70S6K translates mRNA transcripts in the form of 5′TOP motif next to the phosphorylation by mTOR [6]–[7].…”

Turn motif phosphorylation negatively regulates activation loop phosphorylation in Akt

“…Akt regulates diverse cellular functions, including glucose metabolism and cell survival (Fayard et al, 2005;Manning and Cantley, 2007). Dysregulation of Akt has been observed in human diseases, including cancers (Restuccia and Hemmings, 2010). Thus, understanding the molecular mechanism of Akt activation is important for basic biology and therapeutic development.…”