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.
N1 - Publisher Copyright:
© 2014 American Association for Cancer Research.
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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U2 - 10.1158/0008-5472.CAN-14-0747
DO - 10.1158/0008-5472.CAN-14-0747
M3 - Article
C2 - 24994713
AN - SCOPUS:84907055560
SN - 0008-5472
VL - 74
SP - 4731
EP - 4740
JO - Cancer research
JF - Cancer research
IS - 17
ER -