Article
- The EMBO Journal (2007) 26, 4523 - 4534
- doi:10.1038/sj.emboj.7601872
Published online: 11 October 2007
Subject Categories:
The pro-apoptotic kinase Mst1 and its caspase cleavage products are direct inhibitors of Akt1
Bekir Cinar1,2, Ping-Ke Fang1,2, Mohini Lutchman1,2, Dolores Di Vizio1,2, Rosalyn M Adam1,2, Natalya Pavlova3, Mark A Rubin4, Pamela C Yelick5,6 and Michael R Freeman1,2,3
- Urological Diseases Research Center, Department of Urology, Children's Hospital Boston, Boston, MA, USA
- Department of Surgery, Harvard Medical School, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Division of Craniofacial and Molecular Genetics, Department of Oral and Maxillofacial Pathology, Tufts University, Boston, MA, USA
- Division of Craniofacial and Molecular Genetics, Department of Biomedical Engineering, Tufts University, Boston, MA, USA
Correspondence to:
Michael R Freeman, Enders Research Laboratories, Department of Urology, Children's Hospital Boston, suite 1161, 300 Longwood Avenue, Boston, MA 02115, USA. Tel.: +1 617 919 2644; Fax: +1 617 730 0238; E-mail: michael.freeman@childrens.harvard.edu
Received 20 December 2006; Accepted 10 September 2007
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.
Keywords:
- apoptosis,
- kinases,
- lipid rafts,
- prostate cancer,
- protein complex
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