Reference: de Joussineau, C., et al. 2003. Nature. 426:555-559. Filopodia allow epithelia to communicate over long distances. Alexandre/Macmillan

Alpha-catenin has often been considered to be a non-regulatory intercellular adhesion protein, in contrast to beta-catenin, which has well-documented dual roles in cell-cell adhesion and signal transduction. Recently, however, alpha-catenin has been found to be important not only in connecting the E-cadherin-beta-catenin complex to the actin cytoskeleton, but also in coordinating actin dynamics and inversely correlating cell adhesion with proliferation. As the number of alpha-catenin-interacting partners increases, intriguing new connections imply even more complex regulatory functions for this protein.

Cancers display a diverse set of cellular defects, which are thought to be elicited by multiple genetic mutations. In this study, we show that when a single adherens junction protein, ␣-catenin, is removed by conditional targeting, the entire skin epidermis systematically transforms to a hyperproliferative, invasive tissue replete with inflammation. Transcriptional profiling and biochemical analyses reveal that ␣-catenin ablation is accompanied by activation of NF-B and its proinflammatory target genes, along with genes involved in proliferation, wound healing, angiogenesis, and metastasis. Many of these alterations occur in vitro and in the embryo, and thus seem at least partly to be intrinsic to the loss of ␣-catenin. We show that reductions in ␣-catenin, activation of NF-B, and inflammation are common features of human squamous cell carcinomas of the skin.cancer ͉ inflammation ͉ E-cadherin A dherens junctions (AJs) are intercellular junctions prominent in normal epithelia and reduced in cancers. The prototypic transmembrane core of AJs is composed of Ecadherin, whose cytoplasmic domain binds ␤-catenin, which in turn binds ␣-catenin. ␣-Catenin then regulates actin dynamics to integrate AJs with the cytoskeleton and promote intercellular adhesion (1). Throughout development, epithelia also use AJs to coordinate and maintain an intricate balance between intercellular adhesion and growth control. The best-studied mechanism is through Wnt signaling, which stabilizes additional ␤-catenin to serve as a transcription cofactor for the Tcf͞Lef family of DNA binding proteins (2). Among the targets of Tcf͞Lef͞␤-catenin complexes are cell-cycle-regulated genes.Mutations in ␤-catenin, E-cadherin, and ␣-catenin genes have been found in some human cancers, and reduced E-cadherin and ␣-catenin are often prognostic markers of poor clinical outcome in squamous cell carcinomas (SCCs) (2, 3). It has been assumed that reductions in E-cadherin and ␣-catenin act by liberating ␤-catenin, freeing it to trigger Tcf͞Lef-mediated transcription and causing uncontrolled tumor growth (4, 5). Thus it is curious that in skin, 2 days after conditional ablation of ␣-catenin, the epidermis loses polarity and becomes hyperproliferative, yielding large masses that resemble SCC in situ, a precancerous state (6). By contrast, activating mutations in ␤-catenin typically result in benign hair tumors (pilomatricomas) rather than epidermal SCCs (7,8). Such findings cannot be explained by ␣-catenin acting simply as a tumor suppressor to sequester ␤-catenin.This conundrum prompted us to explore how loss of ␣-catenin elicits this phenotype. Here we report that ␣-catenin conditional knockout (cKO) epidermis systematically progresses from a hyperpoliferative adherent tissue to a dermal infiltrate of nonadherent, dysplastic cells. We have also unraveled a link between ␣-catenin and NF-B signaling that unexpectedly points to ␣-catenin at the nexus of additional pathways that go awry in cancers. ResultsProgression to Hyperproliferation and Invasion. K14-Cre͞␣-c...