Co-translational sorting enables a single mRNA to generate distinct polysomes with different localizations and protein fates

β-catenin is a multi-functional protein playing essential roles in cancer. It bridges E-cadherin to the cytoskeleton and also activates transcription in response to Wnt. Plasma membrane β-catenin is stable whereas without Wnt, cytoplasmic β-catenin is degraded by the destruction complex, composed of APC and Axin. Here, we show that APC and Axin associate with many mRNAs and that this occurs via the nascent protein chains. Notably, APC and Axin bind β-catenin mRNAs present as either single polysome or polysome condensates, and co-translational interactions constitute the major fraction of their binding to the β-catenin protein. Remarkably, E-cadherin also binds β-catenin co-translationally, and β-catenin mRNAs localize either with APC in the cytosol or E-cadherin at the plasma membrane. Thus, co-translational interactions sort β-catenin mRNAs into distinct polysome populations that spatially segregate in cells and synthesize proteins with different functions. Co-translational polysome sorting provides a mechanism to regulate the fate of multi-functional proteins.