Cadherin-mediated cell-cell adhesion is perturbed by v-src tyrosine phosphorylation in metastatic fibroblasts.

Abstract

Abstract. Rat 3Y1 cells acquire metastatic potential when transformed with v-src, and this potential is enhanced by double transformation with v-src and v-los (Taniguchi, S., T. Kawano, T. Mitsudomi, G. Kimura, and T. Baba. 1986. Jpn. J. Cancer Res. 77:1193-1197. We compared the activity of cadherin cell adhesion molecules of normal 3Y1 cells with that of v-src transformed (SR3Y1) and v-src and v-los double transformed (fosSR3Y1) 3Y1 cells. These cells expressed similar amounts of P-cadherin, and showed similar rates of cadherin-mediated aggregation under suspended conditions. However, the aggregates or colonies of these cells were morphologically distinct. Normal 3Y1 cells formed compacted aggregates in which cells are firmly connected with each other, whereas the transformed cells were more loosely associated, and could freely migrate out of the colonies. Overexpression of exogenous E-cadherin in these transformed cells had no significant effect on their adhesive properties. We then found that herbimycin A, a tyrosine kinase inhibitor, induced tighter cell-cell associations in the aggregates of the transformed cells. In contrast, vanadate, a tyrosine phosphatase inhibitor, inhibited the cadherin-mediated aggregation of SR3Y1 and fosSR3Y1 cells but had little effect on that of normal 3Y1 cells. These results suggest that v-src-mediated tyrosine phosphorylation perturbs cadherin function directly or indirectly, and the inhibition of tyrosine phosphorylation restores cadherin action to the normal state. We next studied tyrosine phosphorylation on cadherins and the cadherin-associated proteins, catenins. While similar amounts of catenins were expressed in all of these cells, the 98-kD catenin was strongly tyrosine phosphorylated only in SR3Y1 and fosSR3Y1 cells. Cadherins were also weakly tyrosine phosphorylated only in the transformed cells. The tyrosine phosphorylation of these proteins was enhanced by vanadate, and inhibited by herbimycin A. Thus, the tyrosine phosphorylation of the cadherin-catenin system itself might affect its function, causing instable cell-cell adhesion.

Tyrosine phosphorylation of 100-130 kDa proteins in lung cancer correlates with poor prognosis

“…In the huiman gastric cancer cell line, HSC-39, mutation in the f-catenin gene that resulted in complete abolishment of E-cadherin-dependent cell-cell adhesion was observed, and transfection of the f-ctenin gene in the cells fully recovered the cell-cell adhesion (Kawanishi et al, 1995). We have previously reported (Matsuyoshi et al, 1992;Hamaguchi et al, 1993a) that cadherin dependent cell-cell adhesion was strongly erturbed upon tyrosine phosphorylation of f-catenin in RSV-transformed cells where cadherins and catenins were expressed and formed complexes as normal cells. Another pTyr-containing protein, pl20, was also identified as a major pTyr-containing protein in RSVtransformed cells whose phosphorylation closely correlated with cell transformation (Reynolds et al, 1989).…”

“…These proteins were known as major components of the cell adhesion system and their tyrosine phosphorylation showed good correlation with transforming activity of v-Src kinase (Schaller et al, 1992;Illic et al, 1995;Matsuyoshi et al, 1992;Hamaguchi et al, 1988Hamaguchi et al, , 1993aIllic et al, 1995;Reynolds et al, 1989Reynolds et al, , 1992. Thus, tyrosine phosphorylation of these proteins may perturb cell-cell adhesion and activate tumour cell movement, invasion and metastasis.…”

Thrombospondin-1 Induces Tyrosine Phosphorylation of Adherens Junction Proteins and Regulates an Endothelial Paracellular Pathway

“…The phosphotyrosine-containing proteins that we have now demonstrated in ECs exposed to TSP could be immunolocalized to the intercellular boundaries. Several nonreceptor PTKs are preferentially associated with the plasma membrane, including members of the src family (Tsukita et al, 1991;Matsuyoshi et al, 1992;Behrens et al, 1993;Hamaguchi et al, 1993). Src transformation increases tyrosine phosphorylation of cell-cell adherens junction proteins and diminishes cadherin-dependent, homophilic adhesion (Matsuyoshi et al, 1992;Volberg et al, 1992;Behrens et al, 1993;Hamaguchi et al, 1993).…”

Turn‐off, drop‐out: Functional state switching of cadherins

“…This suggests that multiple kinases and phosphatases regulate cadherin function, possibly each playing a role in a specific tissue and at a specific time during development. Overexpression of the nonreceptor tyrosine kinases Src (Matsuyoshi et al, 1992;Hamaguchi et al, 1993;Behrens et al, 1993), and Fer (Rosato et al, 1998) has been demonstrated to increase tyrosine phosphorylation of ␤-catenin (and p120 ctn ). Furthermore, a dominant-negative Src that interferes with function, or a Src-specific tyrosine kinase inhibitor induce cell-cell adhesion (Owens et al, 2000), further suggesting that Src plays an in vivo role in regulating the phosphotyrosine content of ␤-catenin and that suppression of tyrosine phosphorylation of ␤-catenin promotes formation of cadherin-mediated adhesions.…”