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Birchmeier/Macmillan
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8 K5 x# G, K* X# f' M/ pCells 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)., O# m+ n# Q7 e3 x& C p) g
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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.
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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.
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7 V+ @; y/ \$ N% yBirchmeier 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.& K) b# ?* V0 w, E2 U( p. t
0 Y% o6 s: \' j3 z8 QDisruption 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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) O$ B+ e' K2 s& F" w% ?# S1 B+ j9 NFujita, 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
