Journal
EMBO JOURNAL
Volume 26, Issue 21, Pages 4523-4534Publisher
WILEY
DOI: 10.1038/sj.emboj.7601872
Keywords
apoptosis; kinases; lipid rafts; prostate cancer; protein complex
Categories
Funding
- NCI NIH HHS [R01 CA112303] Funding Source: Medline
- NIDDK NIH HHS [P50 DK65298, P50 DK065298, R37 DK047556, R37 DK47556] Funding Source: Medline
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Akt kinases mediate cell growth and survival. Here, we report that a pro-apoptotic kinase, Mst1/STK4, is a physiological Akt1 interaction partner. Mst1 was identified as a component of an Akt1 multiprotein complex isolated from lipid raft-enriched fractions of LNCaP human prostate cancer cells. Endogenous Mst1, along with its paralog, Mst2, acted as inhibitors of endogenous Akt1. Surprisingly, mature Mst1 as well as both of its caspase cleavage products, which localize to distinct subcellular compartments and are not structurally homologous, complexed with and inhibited Akt1. cRNAs encoding full-length Mst1, and N- and C-terminal caspase Mst1 cleavage products, reverted an early lethal phenotype in zebrafish development induced by expression of membrane-targeted Akt1. Mst1 and Akt1 localized to identical subcellular sites in human prostate tumors. Mst1 levels declined with progression from clinically localized to hormone refractory disease, coinciding with an increase in Akt activation with transition from hormone naive to hormone-resistant metastases. These results position Mst1/2 within a novel branch of the phosphoinositide 3-kinase/Akt pathway and suggest an important role in cancer progression.
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