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The type III TGF-β receptor regulates epithelial and cancer cell migration through β-arrestin2-mediated activation of Cdc42
Gerard C. Blobea,b,1
Departments of aMedicine and bPharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27708
Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved March 19, 2009
Received for publication December 17, 2008.
Loss of expression of the TGF-β superfamily coreceptor,the type III TGF-β receptor (TβRIII or betaglycan),occurs in a broad spectrum of human cancers including breast,lung, ovarian, pancreatic, prostate, and renal cell cancer.TβRIII suppresses cancer progression in vivo, at leastin part, by reducing cancer cell motility. However, the mechanismby which TβRIII regulates migration is unknown. Here, wedemonstrate an unexpected TGF-β signaling independent rolefor TβRIII in activating Cdc42, altering the actin cytoskeletonand reducing directional persistence to inhibit random migrationof both cancer and normal epithelial cells. Functionally, TβRIIIthrough its interaction with the scaffolding protein β-arrestin2,activates Cdc42 and inhibits migration. These studies identifya TGF-β independent homeostatic function for TβRIIIin regulating cell migration.
Author contributions: K.M. and G.C.B. designed research; K.M.performed research; K.M. and G.C.B. analyzed data; and K.M.and G.C.B. wrote the paper.