Overexpression of Hakai (right) increases endocytosis and degradation of E-cadherin (white).


Cells come unglued and transition to a more motile phenotype with the help of an E3 ligase, according to new results from Walter Birchmeier and colleagues (Max-Delbrück-Center for Molecular Medicine, Berlin, Germany).

Birchmeier's study focused on cadherins, adhesion molecules that act as anchors via a catenin link to the actin cytoskeleton. During embryogenesis and carcinoma progression, disruption of cadherin-mediated adhesion between epithelial cells helps them make the transition to a more mobile, mesenchymal phenotype. This transition involves endocytosis of cadherin and catenin molecules following phosphorylation by tyrosine kinases such as Src or c-Met.

In the new study, Birchmeier identified a cadherin-binding protein, Hakai, that promotes endocytosis of the cadherin complex, leading to disruption of cell adhesion. Hakai binds to E-cadherin, the prototypical member of the cadherin family, in a phosphorylation-dependent manner. It also competes with other adhesion molecules, such as p120ctn, for E-cadherin binding.

Birchmeier says that “Hakai smelled of degradation,” as it has sequence similarity to c-Cbl, an E3 ligase that ubiquitinates phosphorylated tyrosine kinase receptors and prompts their internalization and degradation. Hakai, which is Japanese for destruction, increases ubiquitination of the E-cadherin complex, particularly when E-cadherin is phosphorylated by Src or in response to growth factors.

Disruption of cell adhesion by Hakai causes cell scattering, similar to that observed during the transition to a mesenchymal phenotype. Birchmeier now plans to test whether Hakai's motility-promoting properties are used by tumor cells to trigger invasion and metastasis.Reference:

Fujita, Y., et al., 2002. Nat. Cell Biol. 10.1038/ncb758.