Integrin α3β1–CD151 complex regulates dimerization of ErbB2 via RhoA

摘要

Integrin 伪3尾1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of 伪3尾1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of 伪3尾1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of 伪3尾1-depleted cells was reproduced upon depletion of tetraspanin CD151 and mirrored that of the cells treated with Herceptin, an established ErbB2 antagonist. Breast cancer cells expressing the 伪3尾1鈥揅D151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with 伪3尾1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in 伪3尾1鈥揅D151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both 伪3尾1 and CD151. We also found that the level of active RhoA was increased in 伪3尾1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of 伪3尾1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of 伪3尾1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the 伪3尾1鈥揅D151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.