pVHL suppresses kinase activity of Akt in a proline-hydroxylation–dependent manner

Abstract

Activation of the serine-threonine kinase Akt promotes the survival and proliferation of various cancers. Hypoxia promotes the resistance of tumor cells to specific therapies. We therefore explored a possible link between hypoxia and Akt activity. We found that Akt was prolyl-hydroxylated by the oxygen-dependent hydroxylase EglN1. The von Hippel–Lindau protein (pVHL) bound directly to hydroxylated Akt and inhibited Akt activity. In cells lacking oxygen or functional pVHL, Akt was activated to promote cell survival and tumorigenesis. We also identified cancer-associated Akt mutations that impair Akt hydroxylation and subsequent recognition by pVHL, thus leading to Akt hyperactivation. Our results show that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering Akt activation, which has a critical role in tumor growth and therapeutic resistance.

A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

“…These mutations and proteins would suggest a model (Figure 7E), whereby mutant IDH1 may lead to high phospho-ERK (Chaturvedi et al, 2013), and SRC can activate PI3K (Chen et al, 2015; Su et al, 2016) and where activated mTOR signaling may activate transcription targets of hypoxia via HIF-1alpha (particularly in the absence of VHL), including NDRG1 and growth factors that may lead to a further increase ERK and PI3K signaling (Clark, 2009). Notably, VHL was recently found to directly suppress AKT activity (Guo et al, 2016), and generation of 2-hydroxyglutarate (2HG) by mutated IDH1/2 was also recently found to lead to the activation of mTOR (Carbonneau et al, 2016); our data here would highlight the importance of both of the above relationships in the setting of human cancer.…”

“…(D) Top differentially expressed proteins in HIGH P-AKT group compared to unaligned and PI3K-altered groups (see Methods), not including core PI3K/AKT/mTOR members. (E) Diagram of interactions involving PI3K/AKT/MTOR pathway represented by selected features from (C) and (D) (Carbonneau et al, 2016; Dodd et al, 2015; Guo et al, 2016; Weiler et al, 2014), with differential protein expression patterns represented, comparing tumors in HIGH P-AKT group with tumors harboring PI3K/RTK genomic alteration or with unaligned tumors. P values by t-test on log-transformed data.…”

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

“…The major molecular sensor of oxygen is the prolyl hydroxylases (PHD), which are inactivated in hypoxic conditions, and in turn impairs prolyl hydroxylation of various cellular substrates, including hypoxia-induced factor alpha (HIFα) and serine/threonine kinase Akt [165, 166]. It is well-established that hydroxylated HIFα is recognized and polyubiquitinated by the tumor suppressor protein pVHL and undergoes proteasome-dependent degradation [167, 168].…”

New Insights into Protein Hydroxylation and Its Important Role in Human Diseases

“…demonstrate that Akt can be hydroxylated on Pro125 and Pro313 residues by PHD2/EglN1 in vivo and in vitro [98]. pVHL binds directly with hydroxylated Akt and inhibits Akt activity, demonstrated by the decrease of Akt phosphorylation on threonine 308 (Thr308) and serine 473 (Ser473) [98]. Therefore, in cells under hypoxia or lacking functional pVHL, Akt activity is aberrantly elevated, therefore contributing to increased cell proliferation and tumorigenesis (Fig.…”

“…Therefore, in cells under hypoxia or lacking functional pVHL, Akt activity is aberrantly elevated, therefore contributing to increased cell proliferation and tumorigenesis (Fig. 5A and 5B) [98]. Concerning the disease relevance, cancer-associated AKT mutations have been found to decrease Akt hydroxylation, therefore contributing to higher Akt phosphorylation.…”