MPZL1 forms a signalling complex with GRB2 adaptor and PTPN11 phosphatase in HER2-positive breast cancer cells

HER2/ErbB2 is overexpressed in a significant fraction of breast tumours and is associated with a poor prognosis. The adaptor protein GRB2 interacts directly with activated HER2 and is sufficient to transmit oncogenic signals. However, the consequence of HER2 activation on global GRB2 signalling networks is poorly characterized. We performed GRB2 affinity purification combined with mass spectrometry analysis of associated proteins in a HER2+ breast cancer model to delineate GRB2-nucleated protein interaction networks. We report the identification of the transmembrane protein MPZL1 as a new GRB2-associated protein. Our data show that the PTPN11 tyrosine phosphatase acts as a scaffold to bridge the association between GRB2 and MPZL1 in a phosphotyrosine-dependent manner. We further demonstrate that the formation of this MPZL1-PTPN11-GRB2 complex is triggered by cell attachment to fibronectin. Thus, our data support the importance of this new signalling complex in the control of cell adhesion of HER2+ breast cancer cells, a key feature of the metastatic process.