Hsp70-Bag3 interactions regulate cancer-related signaling networks

Teresa A. Colvin; Vladimir L. Gabai; Jianlin Gong; Stuart K. Calderwood; Hu Li; Suryaram Gummuluru; Olga N. Matchuk; Svetlana G. Smirnova; Nina V. Orlova; Irina A. Zamulaeva; Mikel Garcia-Marcos; Xiaokai Li; Z. T. Young; Jennifer N. Rauch; Jason E. Gestwicki; Shinichi Takayama; Michael Y. Sherman

doi:10.1158/0008-5472.CAN-14-0747

Hsp70-Bag3 interactions regulate cancer-related signaling networks

Teresa A. Colvin, Vladimir L. Gabai, Jianlin Gong, Stuart K. Calderwood, Hu Li, Suryaram Gummuluru, Olga N. Matchuk, Svetlana G. Smirnova, Nina V. Orlova, Irina A. Zamulaeva, Mikel Garcia-Marcos, Xiaokai Li, Z. T. Young, Jennifer N. Rauch, Jason E. Gestwicki, Shinichi Takayama, Michael Y. Sherman

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136 Scopus citations

Abstract

Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.

Original language	English
Pages (from-to)	4731-4740
Number of pages	10
Journal	Cancer Research
Volume	74
Issue number	17
DOIs	https://doi.org/10.1158/0008-5472.CAN-14-0747
State	Published - 1 Sep 2014
Externally published	Yes

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Colvin, T. A., Gabai, V. L., Gong, J., Calderwood, S. K., Li, H., Gummuluru, S., Matchuk, O. N., Smirnova, S. G., Orlova, N. V., Zamulaeva, I. A., Garcia-Marcos, M., Li, X., Young, Z. T., Rauch, J. N., Gestwicki, J. E., Takayama, S., & Sherman, M. Y. (2014). Hsp70-Bag3 interactions regulate cancer-related signaling networks. Cancer Research, 74(17), 4731-4740. https://doi.org/10.1158/0008-5472.CAN-14-0747

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title = "Hsp70-Bag3 interactions regulate cancer-related signaling networks",

abstract = "Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.",

author = "Colvin, {Teresa A.} and Gabai, {Vladimir L.} and Jianlin Gong and Calderwood, {Stuart K.} and Hu Li and Suryaram Gummuluru and Matchuk, {Olga N.} and Smirnova, {Svetlana G.} and Orlova, {Nina V.} and Zamulaeva, {Irina A.} and Mikel Garcia-Marcos and Xiaokai Li and Young, {Z. T.} and Rauch, {Jennifer N.} and Gestwicki, {Jason E.} and Shinichi Takayama and Sherman, {Michael Y.}",

note = "Publisher Copyright: {\textcopyright} 2014 American Association for Cancer Research.",

year = "2014",

month = sep,

day = "1",

doi = "10.1158/0008-5472.CAN-14-0747",

language = "אנגלית",

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Colvin, TA, Gabai, VL, Gong, J, Calderwood, SK, Li, H, Gummuluru, S, Matchuk, ON, Smirnova, SG, Orlova, NV, Zamulaeva, IA, Garcia-Marcos, M, Li, X, Young, ZT, Rauch, JN, Gestwicki, JE, Takayama, S & Sherman, MY 2014, 'Hsp70-Bag3 interactions regulate cancer-related signaling networks', Cancer Research, vol. 74, no. 17, pp. 4731-4740. https://doi.org/10.1158/0008-5472.CAN-14-0747

TY - JOUR

T1 - Hsp70-Bag3 interactions regulate cancer-related signaling networks

AU - Colvin, Teresa A.

AU - Gabai, Vladimir L.

AU - Gong, Jianlin

AU - Calderwood, Stuart K.

AU - Li, Hu

AU - Gummuluru, Suryaram

AU - Matchuk, Olga N.

AU - Smirnova, Svetlana G.

AU - Orlova, Nina V.

AU - Zamulaeva, Irina A.

AU - Garcia-Marcos, Mikel

AU - Li, Xiaokai

AU - Young, Z. T.

AU - Rauch, Jennifer N.

AU - Gestwicki, Jason E.

AU - Takayama, Shinichi

AU - Sherman, Michael Y.

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.

AB - Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with the SH3 domain of Src, thereby mediating the effects of Hsp70 on Src signaling. Using several complementary approaches, we established that the Hsp70-Bag3 module is a broad-acting regulator of cancer cell signaling by modulating the activity of the transcription factors NF-κB, FoxM1, Hif1α, the translation regulator HuR, and the cell-cycle regulators p21 and survivin. We also identified a small-molecule inhibitor, YM-1, that disrupts the Hsp70-Bag3 interaction. YM-1 mirrored the effects of Hsp70 depletion on these signaling pathways, and in vivo administration of this drug was sufficient to suppress tumor growth in mice. Overall, our results defined Bag3 as a critical factor in Hsp70-modulated signaling and offered a preclinical proof-of-concept that the Hsp70-Bag3 complex may offer an appealing anticancer target.

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Hsp70-Bag3 interactions regulate cancer-related signaling networks

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