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Open Access Research article

Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein

Longzhen Piao19, Yuwen Li1, Keum-Jin Yang1, Kyeong Ah Park1, Hee Sun Byun1, Minho Won1, Janghee Hong1, Jeong-Lan Kim2, Gi Ryang Kweon3, Gang Min Hur1, Jeong Ho Seok1, Jae Youl Cho4, Taehoon Chun5, Daniel Hess6, Ragna Sack6, Sauveur-Michel Maira7, Derek P Brazil8, Brian A Hemmings6 and Jongsun Park1*

Author Affiliations

1 Department of Pharmacology, Daejeon Regional Cancer Center, Cancer Research Institute, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Taejeon, 301-131, Korea

2 Department of Psychiatry, College of Medicine, Chungnam National University, Taejeon, 301-131, Korea

3 Department of Biochemistry, College of Medicine, Chungnam National University, Taejeon, 301-131, Korea

4 School of Bioscience and Biotechnology, and Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon, 200-701, Korea

5 Division of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seoul, 136-701, Korea

6 Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4058 Basel, Switzerland

7 Novartis Institutes for Biomedical Research, Oncology Disease Area, Novartis Pharma AG, CH4002 Basel, Switzerland

8 UCD Diabetes Research Centre, UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

9 Department of Internal Oncology, Affiliated Hospital of Yanbian University College of Medicine, Yanji 133000, Jilin Province, PR China

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BMC Cell Biology 2009, 10:53  doi:10.1186/1471-2121-10-53

Published: 15 July 2009

Abstract

Background

The serine/threonine protein kinase B (PKB/Akt) is involved in insulin signaling, cellular survival, and transformation. Carboxyl-terminal modulator protein (CTMP) has been identified as a novel PKB binding partner in a yeast two-hybrid screen, and appears to be a negative PKB regulator with tumor suppressor-like properties. In the present study we investigate novel mechanisms by which CTMP plays a role in apoptosis process.

Results

CTMP is localized to mitochondria. Furthermore, CTMP becomes phosphorylated following the treatment of cells with pervanadate, an insulin-mimetic. Two serine residues (Ser37 and Ser38) were identified as novel in vivo phosphorylation sites of CTMP. Association of CTMP and heat shock protein 70 (Hsp70) inhibits the formation of complexes containing apoptotic protease activating factor 1 and Hsp70. Overexpression of CTMP increased the sensitivity of cells to apoptosis, most likely due to the inhibition of Hsp70 function.

Conclusion

Our data suggest that phosphorylation on Ser37/Ser38 of CTMP is important for the prevention of mitochondrial localization of CTMP, eventually leading to cell death by binding to Hsp70. In addition to its role in PKB inhibition, CTMP may therefore play a key role in mitochondria-mediated apoptosis by localizing to mitochondria.