Mice come unstuck

Abstract

Knock out a protein involved in cell adhesion and you'd expect a loss of cell adhesion, right? In the case of α-catenin, you get much more. Normally a component of adherens junctions, α-catenin links the actin cytoskeleton to E-cadherin through β-catenin. Although β-catenin has long been known to play an essential role in Wingless signalling as well as adhesion, α-catenin was thought only to be important in adhesion.As α-catenin is required for early development, Vasloukhin et al.[1xHyperproliferation and defects in epithelial polarity upon conditional ablation of α-catenin in skin. Vasloukhin, V. et al. Cell. 2001; 104: 605–617Abstract | Full Text | Full Text PDF | PubMed | Scopus (276)See all References][1] used a conditional mouse knockout system to remove α-catenin only from epithelial tissues. The α-catenin-null epithelia showed several interesting phenotypes. First, α-catenin-null cells showed a general loss of adhesion, with disrupted epithelial sheets. The cells also had defects in cell polarity, which supports previous work in Drosophila showing that disruption of adherens junctions causes cells to lose their ability to divide correctly in the epithelial plane [2xAdherens junctions inhibit asymmetric cell division in Drosophila epithelium. Lu, B. et al. Nature. 2001; 409: 522–525CrossRef | PubMed | Scopus (184)See all References][2]. This possibly explains some of the defects seen. The epithelial morphology also closely resembled that of pre-cancerous squamous cell carcinomas.Second, the cells showed an increase in proliferation, with many multinucleate cells and dividing cells visible in normally undividing layers, suggesting unregulated mitosis. This was further highlighted in extracted α-catenin-null keratinocytes, which showed rapid growth and poor contact inhibition. The authors suggest that this increased proliferation is not simply due to lack of adhesion because conditional desmoplakin knockouts (which disrupt desmosome-based adhesion) show similar loss of adhesion phenotypes but no extra proliferation. Furthermore, this excess proliferation still occurs in α-catenin-null keratinocytes even in low Ca [2xAdherens junctions inhibit asymmetric cell division in Drosophila epithelium. Lu, B. et al. Nature. 2001; 409: 522–525CrossRef | PubMed | Scopus (184)See all References][2]? conditions where desmosomes and adherens junctions cannot form between cells. In pursuing this excess proliferation, the authors discovered that the α-catenin-null keratinocytes show increased sensitivity to insulin and insulin-like growth factor 1 (IGF-1) and showed increased Ras–mitogen-activated protein kinase (MAPK) activity.They also show that, in α-catenin-null keratinocytes, E-cadherin interacts with insulin receptor substrate 1 (IRS-1), a phenomenon that has also been observed in certain colon cancer cell lines [3xInsulin-like growth factor 1 regulates the location, stability, and transcriptional activity of β-catenin. Playford, M.P. et al. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 12103–12108CrossRef | PubMed | Scopus (184)See all References][3]. The authors suggest that this could account for the increased Ras–MAPK activation seen. Exactly how this increased insulin/IGF-1 sensitivity occurs remains unclear, especially as the authors found no increase in receptor tyrosine kinase activity. If this E-cadhein–IRS-1 complex is somehow rerouting a signalling cascade, it will no doubt be the subject of future study and could prove to be important for models of colon cancer.