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

J Ren1, A Bharti, D Raina

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

Oncogene
|September 15, 2005
PubMed

Insights

MUC1 protein targets cancer cell mitochondria via HSP70/HSP90 chaperones, blocking apoptosis. This pathway involves ErbB receptor and c-Src activation, crucial for cancer progression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Biology

Background:

  • MUC1 is overexpressed in human carcinomas.
  • MUC1's C-terminal subunit localizes to mitochondria, inhibiting apoptosis.
  • The mechanism of MUC1 mitochondrial delivery is unknown.

Purpose of the Study:

  • To elucidate the mechanism of MUC1 delivery to mitochondria.
  • To identify proteins involved in MUC1 mitochondrial transport.

Main Methods:

  • In vitro binding assays for MUC1 cytoplasmic domain with HSP70.
  • Cell-based assays to study MUC1 phosphorylation and binding to HSP90.
  • Western blotting and inhibitor studies targeting c-Src and HSP90.
  • Heregulin (HRG) stimulation of ErbB receptors.

Main Results:

  • MUC1 forms intracellular complexes with HSP70 and HSP90.
  • MUC1 cytoplasmic domain binds directly to HSP70.
  • c-Src-mediated phosphorylation induces MUC1 binding to HSP90.
  • HRG activates c-Src, enhancing MUC1-HSP90 binding and mitochondrial targeting.
  • Inhibitors of c-Src or HSP90 block HRG-induced MUC1 mitochondrial delivery.

Conclusions:

  • MUC1 is delivered to mitochondria via a pathway involving ErbB receptor-c-Src activation.
  • The HSP70/HSP90 chaperone complex transports MUC1 to the mitochondrial outer membrane.
  • This mechanism is critical for MUC1's role in blocking apoptosis in cancer cells.

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