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

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-Exo70 interaction is selectively disrupted, delivery of the metalloprotease MT1-MMP to podosomes, collagen degradation and haptotaxis through basement membrane matrix were impaired. Interacting partners of GIV 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 the ability of GIV to fuel metastasis.