Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGFβ (transforming growth factor β) superfamily co-receptor, TβRIII (type III TGFβ receptor; also known as betaglycan), regulates cell adhesion, migration and invasion, and suppresses cancer progression, in part, through activation of the smallGTPase Cdc42 (cell division cycle 42), and Cdc42-dependent alterations to the actin cytoskeleton. In the present study we demonstrate that TβRIII specifically promotes filopodial formation and extension in MCF10A and HMEC (human mammary epithelial cell) mammary epithelial cells. Mechanistically, cell-surface TβRIII and Cdc42 co-localize to filopodial structures and co-complex in a β-Arrestin2-dependent, and a TβRI/TβRII- independent manner. The β-Arrestin2-mediated interaction between TβRIII and Cdc42 increases complex formation between theCdc42 effectors IRSp53 with N-WASP (neuronal Wiskott-Aldrich syndrome protein) to increase filopodial formation. We demonstrate a function link between filopodial structures and epithelial cell adhesion as regulated by the TβRIII-Cdc42 interaction. The present studies identify TβRIII as a novel regulator of IRSp53/N-WASP via Cdc42 to regulate filopodial formation and cell adhesion. © 2013 Biochemical Society.