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GIV/Girdin activates Gαi and inhibits Gαs via the same motif
Contributed by Marilyn G. Farquhar, June 20, 2016 (sent for review November 28, 2015); reviewed by Kendall J. Blumer, Vladimir L. Katanaev, and David P. Siderovski

Significance
Guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein (GIV)/Girdin has previously been shown to serve as a guanine nucleotide exchange factor (GEF) for the Gα activity-inhibiting polypeptide 1 (Gαi) via a conserved motif in its C terminus. Here we show that this motif serves as a guanine nucleotide dissociation inhibitor (GDI) for Gαs. Sequential phosphorylation of two serine residues that flank this motif by two kinases, cyclin-dependent kinase 5 and PKCθ, ensures that GIV exerts its GEF and GDI activities on Gαi and Gαs, respectively, in a temporally and spatially segregated manner. Through its bifunctional role as GEF and GDI, GIV serves as a pleiotropically acting G-protein modulator that integrates, reinforces, and compartmentalizes signals downstream of both growth factors and G proteins and orchestrates migration–proliferation dichotomy.
Abstract
We previously showed that guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein (GIV), a guanine-nucleotide exchange factor (GEF), transactivates Gα activity-inhibiting polypeptide 1 (Gαi) proteins in response to growth factors, such as EGF, using a short C-terminal motif. Subsequent work demonstrated that GIV also binds Gαs and that inactive Gαs promotes maturation of endosomes and shuts down mitogenic MAPK–ERK1/2 signals from endosomes. However, the mechanism and consequences of dual coupling of GIV to two G proteins, Gαi and Gαs, remained unknown. Here we report that GIV is a bifunctional modulator of G proteins; it serves as a guanine nucleotide dissociation inhibitor (GDI) for Gαs using the same motif that allows it to serve as a GEF for Gαi. Upon EGF stimulation, GIV modulates Gαi and Gαs sequentially: first, a key phosphomodification favors the assembly of GIV–Gαi complexes and activates GIV’s GEF function; then a second phosphomodification terminates GIV’s GEF function, triggers the assembly of GIV–Gαs complexes, and activates GIV’s GDI function. By comparing WT and GIV mutants, we demonstrate that GIV inhibits Gαs activity in cells responding to EGF. Consequently, the cAMP→PKA→cAMP response element-binding protein signaling axis is inhibited, the transit time of EGF receptor through early endosomes are accelerated, mitogenic MAPK–ERK1/2 signals are rapidly terminated, and proliferation is suppressed. These insights define a paradigm in G-protein signaling in which a pleiotropically acting modulator uses the same motif both to activate and to inhibit G proteins. Our findings also illuminate how such modulation of two opposing Gα proteins integrates downstream signals and cellular responses.
- heterotrimeric G proteins
- cAMP
- cancer invasion
- growth factor receptor tyrosine kinase
- guanine nucleotide dissociation inhibitor
Footnotes
↵1Present address: Department of Chemistry and Biochemistry, California State University, Long Beach, CA 90840.
- ↵2To whom correspondence may be addressed. Email: mfarquhar{at}ucsd.edu or prghosh{at}ucsd.edu.
Author contributions: V.G., D.B., A.L., N.A., K.K.M., I.-C.L., J.E., I.L.-S., M.G.-M., M.G.F., and P.G. designed research; V.G., D.B., A.L., N.A., K.K.M., I.-C.L., J.E., I.N., I.L.-S., M.G.-M., and P.G. performed research; J.B.B.-C., M.v.Z., M.G.F., and P.G. contributed new reagents/analytic tools; V.G., D.B., A.L., N.A., K.K.M., I.-C.L., J.E., I.N., I.L.-S., M.v.Z., M.G.-M., M.G.F., and P.G. analyzed data; M.G.F. and P.G. supervised all parts of the work; and M.G.-M., M.G.F., and P.G. wrote the paper.
Reviewers: K.J.B., Washington University School of Medicine; V.L.K., University of Lausanne; and D.P.S., West Virginia University.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1609502113/-/DCSupplemental.
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