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 beta-catenin, a known substrate for both Cdk2 and SHP-1. In the plasma membranes and endosome fractions, beta-catenin is associated with CEACAM1, also known as regulator of insulin clearance. We show that beta-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/beta-catenin/CEACAM1 axis, and show for the first time that Cdk2 has the capacity to regulate insulin internalization. (C) 2011 Elsevier Inc. All rights reserved.