PI3K Transduces AKT-Independent Oncogenic Signaling via SGK3 and INPP4B

Oncogenic mutations in PIK3CA, which encodes the p110α catalytic subunit of PI3K, are frequently detected in breast cancer and have been shown to play a role in driving cell proliferation, survival, and metastasis. Signaling downstream of PIK3CA is mediated by the generation of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P₂) and phosphatidylinositol-3,4,5-trisphosphate, which activate downstream effector kinases, in particular AKT. However, recent findings have shown that PI3KCA-mutant cells with low AKT levels are dependent on serum/glucocorticoid-regulated kinase 3 (SGK3), which shares a consensus phosphorylation motif with AKT, prompting Gasser and colleagues to investigate the mechanisms by which PIK3CA activates SGK3 in breast cancer. Analysis of human breast tumors revealed that SGK3 resides within an amplified genomic peak and is hyperactivated in breast cancer cells harboring PI3KCA/PTEN mutation and increased expression of inositol polyphosphate-4-phosphatase type II (INPP4B), which dephosphorylates PtdIns-3,4-P₂ to generate phosphatidylinositol-3-phosphate (PtdIns-3-P). INPP4B-mediated production of PtdIns-3-P was necessary and sufficient for PI3K-driven SGK3 activation. Functionally, expression of SGK3 in breast cancer cell lines with high INPP4B levels promoted anchorage-independent growth, three-dimensional colony formation, invasive migration, and xenograft tumor growth. Furthermore, silencing of SGK3 increased the level of NMYC downstream regulated 1 (NDRG1) protein, a known metastasis suppressor and SGK3 substrate. Biochemical characterization of breast cancer cell lines revealed that SGK3-mediated phosphorylation primed NDRG1 for subsequent phosphorylation by GSK3β, resulting in NDRG1 ubiquitination and proteasomal degradation via interaction with the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBXW7). Importantly, SGK3-driven degradation of NDRG1 enhanced breast cancer cell migration. Together, these results identify INPP4B-dependent activation of SGK3 as an alternative mechanism by which oncogenic PI3KCA drives tumorigenesis in the absence of AKT activity and suggest that SGK3 inhibition may be effective in PIK3CA-mutant breast cancer.

Gasser JA, Inuzuka H, Lau AW, Wei W, Beroukhim R, Toker A. SGK3 mediates INPP4B-dependent PI3K signaling in breast cancer. Mol Cell 2014 Oct 30 [Epub ahead of print].