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


CONCLUSIONS
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.
Piao
Longzhen
L
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. plz1978@hanmail.net
Li
Yuwen
Y
Yang
Keum-Jin
KJ
Park
Kyeong Ah
KA
Byun
Hee Sun
HS
Won
Minho
M
Hong
Janghee
J
Kim
Jeong-Lan
JL
Kweon
Gi Ryang
GR
Hur
Gang Min
GM
Seok
Jeong Ho
JH
Cho
Jae Youl
JY
Chun
Taehoon
T
Hess
Daniel
D
Sack
Ragna
R
Maira
Sauveur-Michel
SM
Brazil
Derek P
DP
Hemmings
Brian A
BA
Park
Jongsun
J
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000737:chemistry; D010766:Phosphorylation; D019311:Staurosporine / Q000494:pharmacology; D013869:Thiolester Hydrolases; D014638:Vanadates / Q000494:pharmacology
C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053477:Apoptotic Protease-Activating Factor 1; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D008565:Membrane Proteins; C076715:pervanadate; D014638:Vanadates; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases; D019311:Staurosporine