The type III TGFß receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells.

ABSTRACT

Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGFß (transforming growth factor ß) superfamily co-receptor, TßRIII (type III TGFß receptor; also known as ßglycan), regulates cell adhesion, migration and invasion, and suppresses cancer progression, in part, through activation of the small GTPase Cdc42 (cell division cycle 42), and Cdc42-dependent alterations to the actin cytoskeleton. In the present study we demonstrate that TßRIII specifically promotes filopodial formation and extension in MCF10A and HMEC (human mammary epithelial cell) mammary epithelial cells. Mechanistically, cell-surface TßRIII and Cdc42 co-localize to filopodial structures and co-complex in a ß-arrestin2-dependent, and a TßRI/TßRII-independent manner. The ß-arrestin2-mediated interaction between TßRIII and Cdc42 increases complex formation between the Cdc42 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 TßRIII-Cdc42 interaction. The present studies identify TßRIII as a novel regulator of IRSp53/N-WASP via Cdc42 to regulate filopodial formation and cell adhesion.