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MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90

Oncogene volume 25, pages 20–31 (2006)Cite this article

Abstract

The MUC1 heterodimeric transmembrane glycoprotein is aberrantly overexpressed by most human carcinomas. The MUC1 C-terminal subunit localizes to mitochondria and blocks stress-induced activation of the intrinsic apoptotic pathway. How MUC1 is delivered to mitochondria is not known. The present studies demonstrate that MUC1 forms intracellular complexes with HSP70 and HSP90. We show that the MUC1 cytoplasmic domain binds directly to HSP70 in vitro. By contrast, binding of MUC1 to HSP90 in vitro is induced by c-Src-mediated phosphorylation of the MUC1 cytoplasmic domain. c-Src also increases binding of MUC1 to HSP90 in cells. In concert with these results, we show that heregulin (HRG), a ligand for ErbB receptors, activates c-Src and, in turn, stimulates binding of MUC1 to HSP90. We also show that inhibitors of c-Src or HSP90 block HRG-induced targeting of MUC1 to mitochondria and integration of MUC1 into the mitochondrial outer membrane. These findings indicate that MUC1 is delivered to mitochondria by a mechanism involving activation of the ErbB receptor → c-Src pathway and transport by the molecular chaperone HSP70/HSP90 complex.

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Acknowledgements

This work was supported by Grant CA97098 awarded by the National Cancer Institute. We acknowledge Drs Y Nakatani and J Swada for the pOZ-N vector and helpful advice, and also Kamal Chauhan for technical support.

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Author notes

  1. A Bharti

    Present address: Boston University School of Medicine, Boston, MA, 02118, USA

  2. J Ren and A Bharti: These two authors contributed equally to this work.

Authors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, MA, USA

    J Ren, A Bharti, D Raina, W Chen, R Ahmad & D Kufe

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  1. J Ren
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Correspondence to D Kufe.

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Ren, J., Bharti, A., Raina, D. et al. MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 25, 20–31 (2006). https://doi.org/10.1038/sj.onc.1209012

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