The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

Abstract

Adherens junctions (AJs) are essential for the maintenance of epithelial homeostasis and a key factor in the regulation of cell migration and tumor progression. AJs maintain cell-cell adhesion by linking transmembrane proteins to the actin cytoskeleton. Additionally, they participate in recruitment of signaling receptors and cytoplasmic proteins to the membrane. During cellular invasion or migration, AJs are dynamically regulated and their composition modified to initiate changes in signaling pathways and cytoskeleton organization involved in cellular motility. Loss of E-cadherin, a key component of AJs, is characteristic of epithelial-mesenchymal-transition (EMT) and is associated with tumor cell invasion. We will review recent findings describing novel mechanisms involved in E-cadherin transcription regulation, endocytosis of E-cadherin and signaling associated with loss of AJs as well as reorganization of the AJ during EMT.

Figure 1. Endocytosis pathways involved in the regulation of E-cadherin. Non-clathrin mediated endocytosis can be regulated by scaffolding microdomains, PrP and Reggie/Flotillin or caveolae compared with clathrin-mediated endocytosis. Phosphorylation of E-cadherin at Tyr755 and 756, e.g., by Src, induces its endocytosis and degradation by the proteasome complex after ubiquitination by Hakai or Mdm2.

Figure 2. Reggie/Flotillin-dependent endocytosis of E-cadherin. Reggies/Flotillins regulates E-cadherin endocytosis through macropinocytosis and the recycling of E-cadherin. EGFR can phosphorylate reggie/flotillins preventing their action and thereby inducing the degradation of E-cadherin.

Figure 3. Schematics of clathrin-mediated endocytosis of E-cadherin and role of adaptator proteins Dab2 and Numb. Numb interacts with E-cadherin and binds to the polarity complex protein aPKC/PAR3/PAR6. Upon EMT-induction by HGFR signaling the complex shifts to Numb aPKC/PAR3 promoting endocytosis of E-cadherin. aPKC can decrease binding of Numb to p120 by phosphorylation of E-cadherin and reduce endocytosis of E-cadherin. Numb prevents the activation of Rac1. Dab2 participates in the endocytosis of TβRII and promotes signaling of TGFβ through canonical Smad signaling. TGFβ signaling itself can induce expression of Dab2 by inducing phosphorylation of hnRNPE1, displacing it from the Bat element in Dab2 promoter, through Akt2.