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

Research output: Contribution to journalArticle

73 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 languageEnglish (US)
Pages (from-to)4731-4740
Number of pages10
JournalCancer research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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