Signaling from the adherens junction

Abstract

The cadherin/catenin complex organizes to form a structural Velcro that joins the cytoskeletal networks of adjacent cells. Functional loss of this complex arrests the development of normal tissue organization, and years of research have gone into teasing out how the physical structure of adhesions conveys information to the cell interior. Evidence that most cadherin-binding partners also localize to the nucleus to regulate transcription supports the view that cadherins serve as simple stoichiometric inhibitors of nuclear signals. However, it is also clear that cadherin-based adhesion initiates a variety of molecular events that can ultimately impact nuclear signaling. This chapter discusses these two modes of cadherin signaling in the context of tissue growth and differentiation.

Fig. 8.1

General models of cadherin signaling to the nucleus. Cadherins interact with dual-localization proteins (e.g., β-catenin, Plakoglobin and p120 ctn) that functionally link cadherins to the cortical cytoskeleton and also control the activation of DNA-binding factors in the nucleus. The model presented in a and b reflects evidence that cells with greater cadherin abundance (black bar, b) can sequester, and thereby inhibit, the transcriptional co-activator function of these dual-localization proteins (shown as purple color) better than cells with fewer cadherins (black bar, a). The model presented in c and d reflects evidence that E-cadherin in densely packed epithelial monolayers can inhibit signaling from diverse growth factor receptor kinases (d) better than cells with less mature contacts (c)

Fig. 8.2

Wnt signaling pathway. In the absence of Wnt (left), cytosolic β-catenin is continually phosphorylated by casein kinase 1α (CK1) and glycogen synthase kinase 3β (GSK3β) within an Axin1 scaffold complex. This phosphorylation allows β-catenin to be recognized by a specific E3 ligase (βTrCP, not shown), which catalyzes the ubiquitylation and rapid degradation of β-catenin. The adenomatous polyposis coli (APC) tumor suppressor participates in the phospho-destruction of β-catenin by antagonizing β-catenin de-phosphorylation by phosphatases. During Wnt activation (right), GSK3β activity is inhibited directly by Lrp5/6, which allows β-catenin to accumulate, enter the nucleus, interact with LEF/TCF family members and promote transcription

Fig. 8.3

Density-dependent turnover of cytosolic β-catenin. In densely confluent cells, cadherins promote a faster turnover of β-catenin than in less adhesive (sub-confluent) cells. This may explain why cells migrating adjacent to a wound appear sensitized to Wnt signals. (Figure adapted from Maher et al. 2009)

Fig. 8.4

Armadillo family proteins in cadherin-based adhesion and nuclear signaling. The cadherin cytoplasmic domain binds directly to three distinct armadillo-repeat proteins, β-catenin, Plakoglobin and p120ctn. These proteins play an obligate role in cadherin-based adhesion (Left). To varying degrees, cytoplasmic and nuclear pools of these catenins are generated by Wnt signals, which favors catenin activation of transcription. Cadherins appear to antagonize nuclear catenin functions via both stoichiometric sequestration (left) and catalytic destruction models (right)

Fig. 8.5

E-cadherin is a master initiator of cell–cell contact, junction formation and epithelial polarity. E-cadherin-based adhesion is required for the establishment of diverse cell–cell junctions (e.g., tight junction, zonula adherens junction, desmosomes, gap junctions), as well as signals that require membrane-anchored ligand/receptor interactions (e.g., Notch/Delta, Ephrin/EphR). From this more global viewpoint, “E-cadherin signaling” encompasses signals coming from all of these complexes

Fig. 8.6

E-cadherin and density-dependent inhibition of proliferation. E-cadherin in densely packed epithelial monolayers can inhibit access of EGF to the EGFR as well as downstream signaling from the EGFR (1) compared with less mature contacts (2) E-cadherin engagement can also limit the nuclear accumulation of YAP through a poorly defined mechanism that requires α-catenin (3 and 4)