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GIV is a Non‐Receptor GEF for Gαi with a Unique Motif that Regulates Akt Signaling
Author(s) -
GarciaMarcos Mikel,
Ghosh Pradipta,
Ear Jason,
Farquhar Marilyn Gist
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.879.1
Subject(s) - heterotrimeric g protein , protein kinase b , pi3k/akt/mtor pathway , signal transduction , guanine nucleotide exchange factor , g protein , microbiology and biotechnology , biology , receptor , protein subunit , chemistry , cancer research , biochemistry , gene
Heterotrimeric G proteins are molecular switches that control signal transduction. Ligand‐occupied G‐protein coupled receptors serve are the canonical guanine nucleotide exchange factors (GEFs) that activate heterotrimeric G proteins. A few unrelated non‐receptor GEFs have also been described, but little or nothing is known about their structure, mechanism of action or cellular functions in mammals. We have discovered that GIV/Girdin serves as a non‐receptor GEF for Gαi through an evolutionarily conserved motif that forms a unique interface with the Gα‐subunit. Using insights from the 3‐dimensional structure of this interface, we demonstrate that this GEF motif enhances Akt signaling via the G ??‐PI3K pathway and that mutational disruption of the Gαi‐GIV interface inhibits Akt enhancement and cell migration in cancer cells. Recently we also found that GIV is a metastasis‐related protein in carcinomas by virtue of its ability to promote unrestricted Akt activation. Thus, the novel regulatory motif described here provides the structural and biochemical basis for the pro‐metastatic features of GIV, making the functional disruption of the Gαi‐GIV interface a promising target for therapy against cancer metastasis. Supported by NIH grants CA100768 and DKI7780 to M.G.F, by Basque Government Postdoctoral fellowship BFI06.300 and Susan G. Komen Postdoctoral fellowship KG080079 to MG‐M and by training grant NIH/T32 DK07202 and a Research Scholar Award from American Gastroenterology Association (AGA) to PG.