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

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.

• Authors: Longzhen Piao, Yuwen Li, Keum-Jin Yang, Kyeong Ah Park, Hee Sun Byun, Minho Won, Janghee Hong, Jeong-Lan Kim, Gi Ryang Kweon, Gang Min Hur, Jeong Ho Seok, Jae Youl Cho, Taehoon Chun, Daniel Hess, Ragna Sack, Sauveur-Michel Maira, Derek P Brazil, Brian A Hemmings, Jongsun Park
• Journal: BMC cell biology (BMC Cell Biol) Vol. 10 Pg. 53 (Jul 15 2009) ISSN: 1471-2121 [Electronic] England
• PMID: 19604401 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• APAF1 protein, human
• Adaptor Proteins, Signal Transducing
• Apoptotic Protease-Activating Factor 1
• Enzyme Inhibitors
• HSP70 Heat-Shock Proteins
• Membrane Proteins
• pervanadate
• Vanadates
• THEM4 protein, human
• Thiolester Hydrolases
• Staurosporine

Topics

• Adaptor Proteins, Signal Transducing (analysis, genetics, metabolism)
• Apoptosis
• Apoptotic Protease-Activating Factor 1 (metabolism)
• Cell Line
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation
• HSP70 Heat-Shock Proteins (metabolism)
• HeLa Cells
• Humans
• Membrane Proteins (analysis, genetics, metabolism)
• Mitochondria (chemistry)
• Phosphorylation
• Staurosporine (pharmacology)
• Thiolester Hydrolases
• Vanadates (pharmacology)