Regulation of cadherin stability and turnover by p120ctn: implications in disease and cancer

The strength of cadherin based cell-cell adhesion is modulated by signaling events that control the amount of cadherin present at the cell surface, and the clustering of cadherins into strong adhesive junctions. p120cm has been indirectly implicated in clustering for some time, but it now appears that its main function is to regulate cadherin turnover. Forced p120 downregulation (e.g., by siRNA targeting) results in a striking dose-dependant loss of endogenous cadherins, indicating that p120 is essential for cadherin stability. These data challenge some important paradigms and suggest novel interpretations of existing data. For example, most of the effects of DN-cadherin expression can be accounted for by sequestration of p120. Thus, DN-cadherins phenocopy p120-downregulation, and a significant literature exists already that suggests consequences of p120-deficiency in disease and cancer. Moreover, p120 downregulation occurs frequently in essentially all of the major carcinoma types. Thus, it is possible that the classic observation of E-cadherin-deficiency in metastatic cancer may in some cases be due to p120 downregulation rather than better understood mechanisms acting at the level of E-cadherin transcription. (C) 2004 Elsevier Ltd. All rights reserved.