期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 9, 页码 3178-3183出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900294106
关键词
cell migration; Heterotrimeric G protein; metastasis; PI3K-Akt; RTK
资金
- National Institutes of Health [CA100768, DKI7780, T32 DK07202]
- Basque Government Postdoctoral fellowship [BFI06.300]
- Susan G. Komen Postdoctoral fellowship [KG080079]
- American Gastroenterology Association
Heterotrimeric G proteins are molecular switches that control signal transduction. Ligand-occupied, G protein-coupled receptors serve as the canonical guanine nucleotide exchange factors ( GEFs) that activate heterotrimeric G proteins. A few unrelated nonreceptor 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 nonreceptor GEF for G alpha i through an evolutionarily conserved motif that shares sequence homology with the synthetic GEF peptide KB-752. Using the available structure of the KB-752.G alpha i1 complex as a template, we modeled the G alpha i-GIV interface and identified the key residues that are required to form it. Mutation of these key residues disrupts the interaction and impairs Akt enhancement, actin remodeling, and cell migration in cancer cells. Mechanistically, we demonstrate that the GEF motif is capable of activating as well as sequestering the G alpha-subunit, thereby enhancing Akt signaling via the G beta gamma-PI3K pathway. Recently, GIV has been implicated in cancer metastasis by virtue of its ability to enhance Akt activity and remodel the actin cytoskeleton during cancer invasion. Thus, the novel regulatory motif described here provides the structural and biochemical basis for the prometastatic features of GIV, making the functional disruption of this unique G alpha i-GIV interface a promising target for therapy against cancer metastasis.
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