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- W4365509969 abstract "<div>Abstract<p>The PI3K–AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. Although inhibitors directly targeting the PI3K–AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry–based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2–STAT3 axis as a strategy to treat AKT-driven breast cancer.</p>Significance:<p>AKT binds and phosphorylates SIK1 to overcome SIK1-mediated repression of STAT3, indicating that STAT3 is a potential therapeutic target in breast cancer with hyperactive AKT signaling.</p></div>" @default.
- W4365509969 created "2023-04-15" @default.
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- W4365509969 date "2023-04-14" @default.
- W4365509969 modified "2023-10-16" @default.
- W4365509969 title "Data from AKT Blocks SIK1-Mediated Repression of STAT3 to Promote Breast Tumorigenesis" @default.
- W4365509969 doi "https://doi.org/10.1158/0008-5472.c.6599668.v1" @default.
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