Activation of Galphai3 triggers cell migration via regulation of GIV.
During migration, cells must couple direction sensing to signal transduction and actin remodeling. We previously identified GIV/Girdin as a Galphai3 binding partner. We demonstrate that in mammalian cells Galphai3 controls the functions of GIV during cell migration. We find that Galphai3 preferentially localizes to the leading edge and that cells lacking Galphai3 fail to polarize or migrate. A conformational change induced by association of GIV with Galphai3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of Galphai3 serves as a molecular switch that triggers dissociation of Gbetagamma and GIV from the Gi3-GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. Galphai3-GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the Galphai3-GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration.
Ghosh
Pradipta
P
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Garcia-Marcos
Mikel
M
Bornheimer
Scott J
SJ
Farquhar
Marilyn G
MG
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002465:Cell Movement / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology; D002522:Chlorocebus aethiops; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011487:Protein Conformation; D021381:Protein Transport / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
C502451:CCDC88A protein, human; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D051057:Proto-Oncogene Proteins c-akt; C498819:GNAI3 protein, human; D019206:GTP-Binding Protein alpha Subunits, Gi-Go