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Research Article

GIV/Girdin activates Gαi and inhibits Gαs via the same motif

Vijay Gupta, Deepali Bhandari, Anthony Leyme, Nicolas Aznar, Krishna K. Midde, I-Chung Lo, Jason Ear, Ingrid Niesman, Inmaculada López-Sánchez, Juan Bautista Blanco-Canosa, Mark von Zastrow, Mikel Garcia-Marcos, Marilyn G. Farquhar, and Pradipta Ghosh
PNAS September 27, 2016 113 (39) E5721-E5730; first published September 12, 2016; https://doi.org/10.1073/pnas.1609502113
Vijay Gupta
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
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Deepali Bhandari
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
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Anthony Leyme
bDepartment of Biochemistry, Boston University School of Medicine, Boston, MA 02118;
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Nicolas Aznar
cDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093;
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Krishna K. Midde
cDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093;
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I-Chung Lo
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
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Jason Ear
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
cDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093;
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Ingrid Niesman
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
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Inmaculada López-Sánchez
cDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093;
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Juan Bautista Blanco-Canosa
dDepartment of Chemistry and Molecular Pharmacology, Institute for Research in Biomedicine, 08028 Barcelona, Spain;
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Mark von Zastrow
eDepartment of Psychiatry, University of California, San Francisco, CA 94158
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Mikel Garcia-Marcos
bDepartment of Biochemistry, Boston University School of Medicine, Boston, MA 02118;
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Marilyn G. Farquhar
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
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  • For correspondence: mfarquhar@ucsd.edu prghosh@ucsd.edu
Pradipta Ghosh
aDepartment of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093;
cDepartment of Medicine, University of California, San Diego, La Jolla, CA 92093;
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  • For correspondence: mfarquhar@ucsd.edu prghosh@ucsd.edu
  1. 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

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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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GIV is a GDI for Gαs
Vijay Gupta, Deepali Bhandari, Anthony Leyme, Nicolas Aznar, Krishna K. Midde, I-Chung Lo, Jason Ear, Ingrid Niesman, Inmaculada López-Sánchez, Juan Bautista Blanco-Canosa, Mark von Zastrow, Mikel Garcia-Marcos, Marilyn G. Farquhar, Pradipta Ghosh
Proceedings of the National Academy of Sciences Sep 2016, 113 (39) E5721-E5730; DOI: 10.1073/pnas.1609502113

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GIV is a GDI for Gαs
Vijay Gupta, Deepali Bhandari, Anthony Leyme, Nicolas Aznar, Krishna K. Midde, I-Chung Lo, Jason Ear, Ingrid Niesman, Inmaculada López-Sánchez, Juan Bautista Blanco-Canosa, Mark von Zastrow, Mikel Garcia-Marcos, Marilyn G. Farquhar, Pradipta Ghosh
Proceedings of the National Academy of Sciences Sep 2016, 113 (39) E5721-E5730; DOI: 10.1073/pnas.1609502113
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