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

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

doi:10.1186/1471-2121-10-53

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

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

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

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.

Original language	English
Article number	53
Journal	BMC Cell Biology
Volume	10
DOIs	https://doi.org/10.1186/1471-2121-10-53
Publication status	Published - 2009 Jul 15

Bibliographical note

Funding Information:
We would like to thank P. Cron (FMI, Switzerland) for anti-CTMP antibodies. This work was supported by grants from the Korean government (Ministry of Education, Science and Technology: National Research Foundation of Korea grant (No. 2009-0062916); Ministry for Health, Welfare and Family Affairs: National R&D Program for Cancer Control (No. 0720560)). D. Brazil is supported by Science Foundation Ireland. FMI is part of the Novartis Research Foundation.

ASJC Scopus subject areas

Cell Biology

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Piao, L., Li, Y., Yang, K. J., Park, K. A., Byun, H. S., Won, M., Hong, J., Kim, J. L., Kweon, G. R., Hur, G. M., Seok, J. H., Cho, J. Y., Chun, T., Hess, D., Sack, R., Maira, S. M., Brazil, D. P., Hemmings, B. A., & Park, J. (2009). Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein. BMC Cell Biology, 10, Article 53. https://doi.org/10.1186/1471-2121-10-53

@article{a74a4c5a2cd8490aa9d0ad37f23e4284,

title = "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.",

author = "Longzhen Piao and Yuwen Li and Yang, {Keum Jin} and Park, {Kyeong Ah} and Byun, {Hee Sun} and Minho Won and Janghee Hong and Kim, {Jeong Lan} and Kweon, {Gi Ryang} and Hur, {Gang Min} and Seok, {Jeong Ho} and Cho, {Jae Youl} and Taehoon Chun and Daniel Hess and Ragna Sack and Maira, {Sauveur Michel} and Brazil, {Derek P.} and Hemmings, {Brian A.} and Jongsun Park",

note = "Funding Information: We would like to thank P. Cron (FMI, Switzerland) for anti-CTMP antibodies. This work was supported by grants from the Korean government (Ministry of Education, Science and Technology: National Research Foundation of Korea grant (No. 2009-0062916); Ministry for Health, Welfare and Family Affairs: National R&D Program for Cancer Control (No. 0720560)). D. Brazil is supported by Science Foundation Ireland. FMI is part of the Novartis Research Foundation.",

year = "2009",

month = jul,

day = "15",

doi = "10.1186/1471-2121-10-53",

language = "English",

volume = "10",

journal = "BMC Cell Biology",

issn = "1471-2121",

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T1 - Heat shock protein 70-mediated sensitization of cells to apoptosis by Carboxyl-Terminal Modulator Protein

AU - Piao, Longzhen

AU - Li, Yuwen

AU - Yang, Keum Jin

AU - Park, Kyeong Ah

AU - Byun, Hee Sun

AU - Won, Minho

AU - Hong, Janghee

AU - Kim, Jeong Lan

AU - Kweon, Gi Ryang

AU - Hur, Gang Min

AU - Seok, Jeong Ho

AU - Cho, Jae Youl

AU - Chun, Taehoon

AU - Hess, Daniel

AU - Sack, Ragna

AU - Maira, Sauveur Michel

AU - Brazil, Derek P.

AU - Hemmings, Brian A.

AU - Park, Jongsun

N1 - Funding Information: We would like to thank P. Cron (FMI, Switzerland) for anti-CTMP antibodies. This work was supported by grants from the Korean government (Ministry of Education, Science and Technology: National Research Foundation of Korea grant (No. 2009-0062916); Ministry for Health, Welfare and Family Affairs: National R&D Program for Cancer Control (No. 0720560)). D. Brazil is supported by Science Foundation Ireland. FMI is part of the Novartis Research Foundation.

PY - 2009/7/15

Y1 - 2009/7/15

N2 - 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.

AB - 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.

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U2 - 10.1186/1471-2121-10-53

DO - 10.1186/1471-2121-10-53

M3 - Article

C2 - 19604401

AN - SCOPUS:69249171372

SN - 1471-2121

VL - 10

JO - BMC Cell Biology

JF - BMC Cell Biology

M1 - 53

ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

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