HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

Anutosh Chakraborty, Michael A. Koldobskiy, Katherine M. Sixt, Krishna R. Juluri, Asif K. Mustafa, Adele M. Snowman, Damian B. Van Rossum, Randen L. Patterson, Solomon H. Snyder

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.

Original languageEnglish (US)
Pages (from-to)1134-1139
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number4
DOIs
StatePublished - Jan 29 2008

Fingerprint

Cell Survival
Cell Death
Protein Refolding
HSP90 Heat-Shock Proteins
Inositol
Heat-Shock Proteins
Pharmaceutical Preparations
Proteins
Apoptosis
Drug Therapy
Mutation
Enzymes
Neoplasms
inositol hexakisphosphate kinase
diphosphoric acid
1-diphosphoinositol pentakisphosphate

All Science Journal Classification (ASJC) codes

  • General

Cite this

Chakraborty, A., Koldobskiy, M. A., Sixt, K. M., Juluri, K. R., Mustafa, A. K., Snowman, A. M., ... Snyder, S. H. (2008). HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. Proceedings of the National Academy of Sciences of the United States of America, 105(4), 1134-1139. https://doi.org/10.1073/pnas.0711168105
Chakraborty, Anutosh ; Koldobskiy, Michael A. ; Sixt, Katherine M. ; Juluri, Krishna R. ; Mustafa, Asif K. ; Snowman, Adele M. ; Van Rossum, Damian B. ; Patterson, Randen L. ; Snyder, Solomon H. / HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 4. pp. 1134-1139.
@article{b40105f4787749e39f8f4e373c3b56cf,
title = "HSP90 regulates cell survival via inositol hexakisphosphate kinase-2",
abstract = "Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.",
author = "Anutosh Chakraborty and Koldobskiy, {Michael A.} and Sixt, {Katherine M.} and Juluri, {Krishna R.} and Mustafa, {Asif K.} and Snowman, {Adele M.} and {Van Rossum}, {Damian B.} and Patterson, {Randen L.} and Snyder, {Solomon H.}",
year = "2008",
month = "1",
day = "29",
doi = "10.1073/pnas.0711168105",
language = "English (US)",
volume = "105",
pages = "1134--1139",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "4",

}

Chakraborty, A, Koldobskiy, MA, Sixt, KM, Juluri, KR, Mustafa, AK, Snowman, AM, Van Rossum, DB, Patterson, RL & Snyder, SH 2008, 'HSP90 regulates cell survival via inositol hexakisphosphate kinase-2', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 4, pp. 1134-1139. https://doi.org/10.1073/pnas.0711168105

HSP90 regulates cell survival via inositol hexakisphosphate kinase-2. / Chakraborty, Anutosh; Koldobskiy, Michael A.; Sixt, Katherine M.; Juluri, Krishna R.; Mustafa, Asif K.; Snowman, Adele M.; Van Rossum, Damian B.; Patterson, Randen L.; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 4, 29.01.2008, p. 1134-1139.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HSP90 regulates cell survival via inositol hexakisphosphate kinase-2

AU - Chakraborty, Anutosh

AU - Koldobskiy, Michael A.

AU - Sixt, Katherine M.

AU - Juluri, Krishna R.

AU - Mustafa, Asif K.

AU - Snowman, Adele M.

AU - Van Rossum, Damian B.

AU - Patterson, Randen L.

AU - Snyder, Solomon H.

PY - 2008/1/29

Y1 - 2008/1/29

N2 - Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.

AB - Heat-shock proteins (HSPs) are abundant, inducible proteins best known for their ability to maintain the conformation of proteins and to refold damaged proteins. Some HSPs, especially HSP90, can be antiapoptotic and the targets of anticancer drugs. Inositol hexakisphosphate kinase-2 (IP6K2), one of a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], mediates apoptosis. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. We now show that HSP90 physiologically binds IP6K2 and inhibits its catalytic activity. Drugs and selective mutations that abolish HSP90-IP6K2 binding elicit activation of IP6K2, leading to cell death. Thus, the prosurvival actions of HSP90 reflect the inhibition of IP6K2, suggesting that selectively blocking this interaction could provide effective and safer modes of chemotherapy.

UR - http://www.scopus.com/inward/record.url?scp=39549102614&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39549102614&partnerID=8YFLogxK

U2 - 10.1073/pnas.0711168105

DO - 10.1073/pnas.0711168105

M3 - Article

C2 - 18195352

AN - SCOPUS:39549102614

VL - 105

SP - 1134

EP - 1139

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -