PUBLICATION

The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1

Authors
Cinar, B., Fang, P.K., Lutchman, M., Di Vizio, D., Adam, R.M., Pavlova, N., Rubin, M.A., Yelick, P.C., and Freeman, M.R.
ID
ZDB-PUB-071016-6
Date
2007
Source
The EMBO journal   26(21): 4523-4534 (Journal)
Registered Authors
Cinar, Bekir, Fang, Pingke, Yelick, Pamela C.
Keywords
apoptosis, kinases, lipid rafts, prostate cancer, protein complex
MeSH Terms
  • Animals
  • Apoptosis
  • Caspases/metabolism
  • Cell Line, Tumor
  • Disease Progression
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Membrane Microdomains/chemistry
  • Models, Biological
  • Phenotype
  • Protein Serine-Threonine Kinases/physiology*
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt/physiology*
  • Zebrafish
PubMed
17932490 Full text @ EMBO J.
Abstract
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 naïve 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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping