GIV/Girdin and Exo70 Constitute the Core of the Mammalian Polarized Exocytic Machinery

Abstract

Graphic Abstract: Schematic comparing the components of polarized exocytosis, i.e., the major polarity scaffold in yeast (Bem1p; left) and humans (Girdin; right) and the various cellular components and signaling mechanisms that are known to converge on them. The eTOC blurb (50 words)Polarized exocytosis is a precision-controlled process that is enhanced in disease states, e.g., cancer invasion; what imparts polarity was unknown. Authors reveal how the process underwent an evolutionary upgrade from yeast to humans by pinpointing GIV/Girdin as the polarity scaffold which orchestrates the exocytosis of matrix metalloproteases during cell invasion. HIGHLIGHTS• GIV (human) and Bem1p (yeast) bind Exo70; are required for exocytosis • GIV binds and aids PM localization Exo70 via a conserved short linear motif• Binding facilitates MT1-MMP delivery to podosomes, ECM degradation, invasion• Regulatory control over polarized exocytosis is upgraded during evolution SUMMARY Polarized exocytosis is a fundamental process by which membrane and cargo proteins are delivered to the plasma membrane with precise spatial control; it is essential for cell growth, morphogenesis, and migration.Although the need for the octameric exocyst complex is conserved from yeast to humans, what imparts spatial control is known only in yeast, i.e., a polarity scaffold without mammalian homolog, called Bem1p. We demonstrate that polarity scaffold GIV/Girdin fulfills the key criteria and functions of its yeast counterpart Bem1p. Both Bem1p and GIV bind yeast and mammalian Exo70 proteins via similar short-linear interaction motifs, but each preferentially binds its evolutionary counterpart. In cells where this GIV•Exo-70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. GIV's interacting partners reveal other components of polarized exocytosis in mammals. Findings not only expose how GIV "upgrades" the exocytic process in mammals, but also how the ability to regulate exocytosis shapes GIV's ability to fuel metastasis.