GIV/Girdin and Exo70 Collaboratively Regulate the Mammalian Polarized Exocytic Machinery
Cristina Rohena,
Navin Rajapakse,
I-Chung Lo,
Peter Novick,
Debashis Sahoo,
Pradipta Ghosh
Affiliations
Cristina Rohena
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 232, 239, La Jolla, CA 92093, USA
Navin Rajapakse
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, USA
I-Chung Lo
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, USA
Peter Novick
Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, USA
Debashis Sahoo
Department of Pediatrics, University of California San Diego, San Diego, CA 92093, USA; Department of Computer Science and Engineering, Jacob's School of Engineering, University of California San Diego, San Diego, CA 92093, USA; Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, San Diego, CA 92093, USA
Pradipta Ghosh
Department of Medicine, University of California San Diego, 9500 Gilman Drive (MC 0651), George E. Palade Bldg, Rm 232, 239, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093, USA; Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, San Diego, CA 92093, USA; Veterans Affairs Medical Center, 3350 La Jolla Village Dr, San Diego, CA 92161, USA; Corresponding author
Summary: 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.
