Abstract
The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.
Highlights
The serine–threonine kinase AKT is a non-receptor kinase that plays critical roles in growth and metabolism (Pearce et al, 2010)
All three inhibitors were able to induce near-complete proliferation arrest (Figure 1— figure supplement 7, Figure 1—source data 1). These results demonstrate that allosteric and ATPcompetitive AKT inhibitors differ in their ability to block AKT-mediated survival, and that this survival signal can be mediated by AKT1 or AKT2
Our findings that catalytically inactivating kinase domain mutations (AKT1-K179M, AKT2K181M, AKT2-G161V) or ATP-competitive inhibitor binding to wild-type AKT can promote phosphoinositide binding document the critical importance of the kinase domain conformation on AKT pleckstrin homology (PH)-domain functions
Summary
The serine–threonine kinase AKT is a non-receptor kinase that plays critical roles in growth and metabolism (Pearce et al, 2010). AKT is aberrantly activated in many human cancers, usually due to mutations in upstream components of the Phosphatidyl-Inositol-3-Kinase (PI3K) pathway. AKT signaling is required for tumor maintenance in certain genetic contexts, as has been shown for some cancer cell lines harboring PI3K mutations or amplification of the HER2 receptor tyrosine kinase (She et al, 2008). Encouraged by these results, several ATP-competitive and allosteric AKT inhibitors have been identified (Engelman, 2009), but optimal strategies for the clinical development of these agents are currently unknown
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