Compartmentalized CDK2 is connected with SHP-1 and β-catenin and regulates insulin internalization

The cyclin-dependant kinase CDK2 is compartmentalized in endosomes but its role is poorly understood. Here we show that CDK2 present in hepatic endosome fractions is strictly located in a Triton X-100-resistant environment. The endosomal CDK2 was found to be associated with the protein tyrosine Phosphatase SHP-1, a regulator of Insulin clearance, and the actin anchor β-catenin, a known substrate for both CDK2 and SHP-1. In the plasma membranes and endosome fractions, β-catenin is associated with CEACAM1, also known as regulator of Insulin clearance. We show that β-catenin, not CEACAM1, is a substrate for CDK2. Partial down-modulation of CDK2 in HEK293 cells increased the rate of Insulin internalization. These findings reveal that CDK2 functions, at least in part, via a CDK2/SHP-1/β-catenin/CEACAM1 axis, and show for the first time that CDK2 has the capacity to regulate Insulin internalization.