Adenomatous polyposis coli regulates endothelial cell migration independent of roles in beta-catenin signaling and cell-cell adhesion.
Adenomatous polyposis coli (APC), a tumor suppressor commonly mutated in cancer, is a cytoskeletal organizer for cell migration and a scaffold for GSK3 beta/CKI-mediated phosphorylation and degradation of the Wnt effector beta-catenin. It remains unclear whether these different APC functions are coupled, or independently regulated and localized. In primary endothelial cells, we show that GSK3 beta/CKI-phosphorylated APC localizes to microtubule-dependent clusters at the tips of membrane extensions. Loss of GSK3 beta/CKI-phosphorylated APC from these clusters correlates with a decrease in cell migration. GSK3 beta/CKI-phosphorylated APC and beta-catenin at clusters is degraded rapidly by the proteasome, but inhibition of GSK3 beta/CKI does not increase beta-catenin-mediated transcription. GSK3 beta/CKI-phosphorylated and -nonphosphorylated APC also localize along adherens junctions, which requires actin and cell-cell adhesion. Significantly, inhibition of cell-cell adhesion results in loss of lateral membrane APC and a concomitant increase in GSK3 beta/CKI-phosphorylated APC in clusters. These results uncouple different APC functions and show that GSK3 beta/CKI phosphorylation regulates APC clusters and cell migration independently of cell-cell adhesion and beta-catenin transcriptional activity.
Department of Biology, The James H. Clark Center, Bio-X Program, Stanford University, Stanford, CA 94305, USA.
Elizabeth S
ES
Harris
W James
WJ
Nelson
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D004285:Dogs; D042783:Endothelial Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; D051820:TCF Transcription Factors; D051176:beta Catenin; D047389:Casein Kinase I; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3