Integrin α3β1–CD151 complex regulates dimerization of ErbB2 via RhoA

Abstract

Integrin α3β1 regulates adhesive interactions of cells with laminins and have a critical role in adhesion-dependent cellular responses. Here, we examined the role of α3β1-integrin in ErbB2-dependent proliferation of breast cancer cells in three-dimensional laminin-rich extracellular matrix (3D lr-ECM). Depletion of α3β1 in ErbB2-overexpressing breast cancer cells suppressed growth and restore cell polarity in 3D lr-ECM. The phenotype of α3β1-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 α3β1-CD151 complex have higher steady-state phosphorylation of ErbB2 and show enhanced dimerization of the protein when compared with α3β1-/CD151-depleted cells. Furthermore, Herceptin-dependent dephosphorylation of ErbB2 was only observed in α3β1-CD151-expressing cells. Importantly, the inhibitory activity of Herceptin was more pronounced when cells expressed both α3β1 and CD151. We also found that the level of active RhoA was increased in α3β1- and CD151-depleted cells and that Rho controls dimerization of ErbB2. Expression of α3β1 alone did not have significant prognostic value in patients with invasive ductal carcinoma of the breast. However, expression of α3β1 in combination with CD151 represented a more stringent indicator of poor survival than CD151 alone. Taken together, these results demonstrate that the α3β1-CD151 complex has a critical regulatory role in ErbB2-dependent signalling and thereby may be involved in breast cancer progression.

Tetraspanins at a glance

“…However, so far, there is no evidence that a particular tetraspanin associates directly with these receptors. By contrast, several studies suggest that the underlying mechanisms, at least for CD82, might be indirect (Odintsova et al, 2006) and that the effect of CD151 on the signalling of these receptors might be a consequence of a functional or physical coupling with laminin-binding integrins (Franco et al, 2010;Novitskaya et al, 2014).…”

“…In addition, several tetraspanins, in particular CD9, CD82 and CD151, associate with and/or modulate downstream signalling of tyrosine kinase receptors, including epithelial growth factor receptor (EGFR), ERBB2, c-MET and vascular endothelial growth factor receptor (VEGFR)-3 (also known as FLT4) (Franco et al, 2010;Iwasaki et al, 2013;Murayama et al, 2008;Novitskaya et al, 2014;Odintsova et al, 2003;Sridhar and Miranti, 2006;Takahashi et al, 2007). However, so far, there is no evidence that a particular tetraspanin associates directly with these receptors.…”

Tetraspanins Function as Regulators of Cellular Signaling

“…The authors suggest that integrins are involved in CD9-mediated alterations in RhoA activation by possibly stabilizing integrin-ECM interactions, augmenting RhoA activation. Interestingly, a recent report demonstrates that the loss of CD151 in breast cancer cells resulted in increased RhoA activation as quantified using FRET biosensors (Novitskaya et al, 2014). These data are contrary to Hong et al (2012), who showed no change in Rho activation upon CD151 depletion.…”

α3β1 Integrin Suppresses Prostate Cancer Metastasis via Regulation of the Hippo Pathway

“…Our study contributes to an emerging theme of α3β1 integrin as a moderator of Rho activity. Depleting α3 integrin activates RhoA in breast cancer cells (28) and loss of the α3 partner, tetraspanin CD151, drives Rho-dependent collective invasion (29). Conditional deletion of α3 integrin in mice deregulated Rho activity, disrupting the contractility-relaxation cycle of mammary myoepithelial cells (18) and the morphology of hippocampal neurons (19).…”