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Birchmeier/Macmillan
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0 n" D+ v5 O+ f8 V3 _: D* JCells 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)." d3 y2 A( T9 l" r9 s0 U7 Z
0 y9 }8 z" N/ m9 _4 NBirchmeier'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.0 g0 j) x: l7 Y5 Q6 _
3 l6 g4 u6 h; }/ ~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.3 }9 D* s) G9 i2 e
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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.
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/ W5 l! r& n( y0 K4 eDisruption 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:
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) X7 I# r/ x- z$ f& r( i3 p* \Fujita, Y., et al., 2002. Nat. Cell Biol. 10.1038/ncb758.(Overexpression of Hakai (right) increase) |
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发表于 2009-3-6 00:18
发表于 2015-6-6 09:01
