Apicobasal polarity and Ras/Raf/MEK/ERK signalling in cancer

Many glandular epithelia such as the GI tract are composed of a sheet of cells polarised along their apicobasal axes with the apical membrane facing the lumen of the tube and the basolateral membrane binding to neighbouring cells and the basal extracellular matrix (ECM). Generation of these two membrane domains with distinct cellular macromolecular contents (including proteins and lipids) provides the basic building blocks that support tissue architecture and their various functions.1 The apicobasal polarisation of epithelial cells is a complex and multistage programme controlled by a network of proteins and lipids. It is initiated by cues from the ECM and cell–cell contacts that trigger changes to the cytoskeleton and hence the polarised organisation of endosomal trafficking that sort and deliver proteins and lipids to the apical and basolateral membrane domains. These events lead to the establishment of cell–cell junctional complexes comprising tight and adherens junctions2 (figure 1A). The establishment of polarity also requires the proper assembly and localisation of a set of evolutionarily conserved polarity proteins. These include the Par3/Par6/atypical protein kinase C (aPKC) and Crumbs/protein associated with Caenorhabditis elegans Lin-7 protein (PALS)/PALS1-associated TJ protein (PATJ) complexes that are mainly found apically. The Scribble/discs large (Dlg)/lethal giant larvae (Lgl) complex is located on the lateral surface of the cell2 (figure 1A). Another Par protein is liver kinase b1 (Lkb1, or Par4), which phosphorylates and activates a family of AMP-activated protein kinases to regulate cell growth, metabolism and polarity.1 Class I isoforms of phosphoinositide 3-kinases (PI3K)3 and their antagonising phosphatases phosphatase and tensin homologue4 (PTEN)) and SH2 domain containing inositol 5-phosphatase 25 (SHIP2) are crucial determinants of apicobasal polarity (figure 1A). Figure 1 Disruption of apicobasal polarity in cancer. (A) Major determinants of polarity in epithelial cells. (1) Normal simple glandular epitheliums …