Fig. 3. Oncogenic and tumor-suppressor signaling pathways target cell-polarity mechanisms. (A) Viral E6 oncogene from human HPV targets Dlg and Scrib proteins for ubiquitin-mediated degradation. (B) Activation of TGFβ signaling results in phosphorylation of Par6, and targeting of the E3 ubiquitin ligase Smurf1 to the AJCs, where Smurf1 destroys RhoA, disrupts the integrity of AJCs and causes EMT. (C) Activation of ErbB2 signaling results in disruption of the apical Par6-Par3-aPKC polarity complex by promoting dissociation between Par3 and Par6-aPKC. This function is crucial for ErbB2-mediated disruption of cell polarity and tissue disorganization. (D) The VHL tumor suppressor interacts with core cell-polarity proteins in two ways. First, VHL ubiquitylates active aPKC and targets it for proteasome-mediated degradation. In addition, interaction between VHL and the Par3-Par6-aPKC polarity complex is necessary for correct orientation of the microtubules and for primary cilia formation. (E) The tumor suppressor PTEN is crucial for apical-basal polarization of epithelial cells. During polarization of epithelial cells PTEN is targeted to the future apical membrane domain, where it generates PtdIns(4,5)P₂ (PIP2), which facilitates recruitment of annexin 2 (Anx2), Cdc42 and the apical Par6-Par3-aPKC complex. (F) The tumor suppressor LKB1 controls cell polarity, growth and proliferation by regulating the activities of AMPK and Par1 protein kinases.