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.
Department of Pediatrics, CHUL-CRCHUQ, Quebec, PQ, G1V 4G2, Canada.
Annie
A
Fiset
Elaine
E
Xu
Sébastien
S
Bergeron
André
A
Marette
Georges
G
Pelletier
Katherine A
KA
Siminovitch
Martin
M
Olivier
Nicole
N
Beauchemin
Robert L
RL
Faure
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D003902:Detergents / Q000737:chemistry; D011992:Endosomes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D015703:Antigens, CD; C069847:CD66 antigens; D015815:Cell Adhesion Molecules; D003902:Detergents; D007328:Insulin; D034741:RNA, Small Interfering; D051176:beta Catenin; D051357:Cyclin-Dependent Kinase 2; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6