The roles of cadherins and catenins in cell-cell interactions, tumor growth and metastasis

The Gumbiner laboratory studies the roles of cadherins and catenins in tumor growth and metastasis. In addition to its role in cell adhesion as a cadherin-binding protein, beta-catenin mediates the nuclear signal-transducing events in the Wnt pathway. Beta-catenin signaling is activated in colorectal and other tumor cells, which contributes to tumor growth and progression. Beta-catenin signaling is regulated by a cytoplasmic complex that includes the adenomatous polyposis coli (APC) tumor suppressor protein, axin, and glycogen synthase-kinase. The molecular mechanisms controlling the signaling activity of this pool are being investigated, in particular the relationship between beta-catenin nuclear signaling activity and its function with the cadherins at the cell surface. In colorectal tumor cells, E-cadherin acts as a tumor suppressor protein to slow the proliferation of colon tumor cells by inhibiting the signaling activity of beta-catenin. However, more recent work has revealed that distinct molecular forms of beta-catenin are targeted to adhesive or transcriptional complexes, and the post-translational events regulating these molecular forms are being investigated. Studies are also being done to determine how the APC protein complex regulates beta-catenin targeting, stability, and signaling activity.

Experiments are also being done to understand the role of cadherin signaling in contact inhibition. The loss of E-cadherin expression in late stage tumors leads to increased invasiveness and metastasis. This has always been attributed to the loss of the adhesive function of E-cadherin. However, experiments in the laboratory have shown that the invasion suppressor activity of E-cadherin can be separated from its adhesive function, and instead involves an activity associated with its cytoplasmic domain. Normal cells exhibit a property called contact inhibition of growth, which is often lost in tumor cells. Contact inhibition has been proposed to be mediated by cadherins, but it has been difficult to distinguish a direct role for cadherins from an indirect secondary role resulting from adhesion-mediated alterations in juxtacrine signaling via other receptors. Using purified cadherin proteins to engage cadherins independent of other cell contacts, it has been possible to show that E-cadherin engagement directly inhibits cell growth. The cadherin-dependent signaling pathways responsible for invasion suppression and contact inhibition are being investigated.