Regulation of complexed and free catenin pools by distinct mechanisms. Differential effects of Wnt-1 and v-Src.
Cadherins are transmembrane receptors with an extracellular domain that participates in homophilic cell to cell adhesion and a cytoplasmic domain that associates with proteins called catenins. Cadherin-mediated adhesion as well as adhesion-independent functions for catenins play important roles in differentiation, development, and malignant transformation. Mechanisms that regulate steady-state catenin levels and cadherin-catenin complex stability are poorly understood, but activities of both the Wnt-1 proto-oncogene and tyrosine kinases are implicated. Here I define, at the biochemical level, distinct mechanisms that modulate steady-state catenin levels. Increased cadherin expression, providing more catenin binding sites, leads to selective stabilization of the cadherin-associated population of alpha- and beta-catenin, but not p120(cas). In contrast, expression of Wnt-1 leads primarily to increased stability of the uncomplexed pool of beta-catenin without effect on p120(cas). Significantly, the Wnt-1-induced stabilization of uncomplexed beta-catenin is independent of cadherin expression. Transformation by v-Src does not disrupt the catenin-cadherin complex despite the phosphorylation of E-cadherin and beta-catenin on tyrosine. In contrast to the effects of Wnt-1, v-Src does not modulate the uncomplexed population of beta-catenin. p120(cas) is phosphorylated on tyrosine by v-Src, and this is accompanied by a significant decrease in the level of uncomplexed p120(cas) as well as a change in behavior of p120(cas) upon biochemical fractionation. Taken together these data suggest that p120(cas) and beta-catenin are regulated independently.
Papkoff
J
J
SUGEN, Inc., Redwood City, California 94063, USA.
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006207:Half-Life; D007739:L Cells; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin; D000095002:Delta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin; D015688:Oncogene Protein pp60(v-src); D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse