α6β1 integrin induces proteasome-mediated cleavage of erbB2 in breast cancer cells
- 13 February 2003
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 22 (6), 831-839
- https://doi.org/10.1038/sj.onc.1206203
Abstract
ErbB2 and α6 integrin have been implicated in malignancy of breast cancer cells. Here we have determined the influence of α6β1 integrin on erbB2 signaling in anchorage-independent growth, using MDA-MB435 breast cancer cells. Firstly, we transfected the cells with erbB2 cDNA, and isolated cells with high or low levels of α6β1 integrin by cell sorting (α6H-ErbB and α6L-ErbB). We found that an erbB ligand, heregulin β1, enhanced growth activity of α6L-ErbB cells, but not α6H-ErbB cells. Secondly, we established cells expressing a β4 integrin deletion mutant (β4-Δcyt), which selectively inhibited α6β1 integrin expression and adhesion to laminin-1. Again, heregulin β1 enhanced the growth of erbB2 cDNA-transfected β4-Δcyt cells, but not mock cells. Western blot analysis revealed that heregulin β1 stimulated phosphorylation of Akt and its downstream molecules, GSK3β and p70S6kinase, and that the extent of phosphorylation was greater in ErbB2/β4-Δcyt cells than ErbB2/mock cells. Furthermore, we found that the erbB2 cytoplasmic domain was truncated in ErbB2/mock cells, which was independent of ligand stimulation and adhesion, and was suppressed by proteasome inhibitors. These results suggest that α6β1 integrin inhibits erbB2 signals by inducing proteasome-dependent proteolytic cleavage of the erbB2 cytoplasmic domain, and may thereby contribute to the regulation of tumor growth.Keywords
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