GIV/Girdin and Exo70 Collaboratively Regulate the Mammalian Polarized Exocytic Machinery

Polarized exocytosis is a fundamental process by which membranes and cargo proteins are delivered to the cell surface with precise spatial control. 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 called Bem1p. We demonstrate here that the mammalian scaffold protein, GIV/Girdin, fulfills the key criteria and functions of its yeast counterpart Bem1p; both bind Exo70 proteins via similar short-linear interaction motifs, and each prefers its evolutionary counterpart. Selective disruption of the GIV⋅Exo-70 interaction derails the delivery of the metalloprotease MT1-MMP to invadosomes and impairs collagen degradation and haptotaxis through basement membrane matrix. GIV's interacting partners reveal other components of polarized exocytosis in mammals. Findings expose how the exocytic functions aid GIV's pro-metastatic functions and how signal integration via GIV may represent an evolutionary advancement of the exocytic process in mammals. [Display omitted] ⋅GIV (human) and Bem1p (yeast) bind Exo70 and are required for exocytosis⋅GIV binds and aids PM localization of Exo70 via a conserved short linear motif⋅Binding facilitates MT1-MMP delivery to invadosomes, ECM degradation, and invasion⋅Regulatory control over polarized exocytosis is enriched during evolution Biological Sciences; Cancer; Cell Biology