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Review
. 2015 Mar 13;290(11):6697-704.
doi: 10.1074/jbc.R114.613414. Epub 2015 Jan 20.

GIV/Girdin transmits signals from multiple receptors by triggering trimeric G protein activation

Mikel Garcia-Marcos  1 , Pradipta Ghosh  2 , Marilyn G Farquhar  3
Affiliations
Review

GIV/Girdin transmits signals from multiple receptors by triggering trimeric G protein activation

Mikel Garcia-Marcos et al. J Biol Chem. .

Abstract

Activation of trimeric G proteins has been traditionally viewed as the exclusive job of G protein-coupled receptors (GPCRs). This view has been challenged by the discovery of non-receptor activators of trimeric G proteins. Among them, GIV (a.k.a. Girdin) is the first for which a guanine nucleotide exchange factor (GEF) activity has been unequivocally associated with a well defined motif. Here we discuss how GIV assembles alternative signaling pathways by sensing cues from various classes of surface receptors and relaying them via G protein activation. We also describe the dysregulation of this mechanism in disease and how its targeting holds promise for novel therapeutics.

Keywords: Guanine Nucleotide Exchange Factor (GEF); Heterotrimeric G Protein; Liver Fibrosis; Nephrotic Syndrome; Receptor Tyrosine Kinase; Src Homology 2 Domain (SH2 Domain); Tumor Metastasis.

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Figures

FIGURE 1.
FIGURE 1.
GIV is a multi-modular protein that activates Gαi via its C-terminal GEF motif by assembling a unique GIV-Gαi protein-protein interface. A, schematic representation of the domain organization of GIV. MT, microtubule; GBD, GTPase-binding; PI4P, phosphatidylinositol 4-phosphate; NT, N terminus; CT, C terminus. B, left, homology model of the GEF sequence of GIV (orange) bound to Gαi3 (blue, green, and red) generated as described in Ref. . Green denotes the switch II (SwII) region, and red denotes the α3 helix. Right, same view as is the left panel with a space-filling surface representation of Gαi3 colored by hydrophobicity (red to blue scale indicates increasing hydrophobicity). Three hydrophobic residues in GIV (Leu-1682, Phe-1685, and Leu-1686) are predicted to dock onto a hydrophobic cleft on Gαi3.
FIGURE 2.
FIGURE 2.
The GEF motif of GIV modulates key signaling networks downstream of diverse classes of receptors. Top, a schematic summarizing the diverse classes of receptors that converge upon GIV and have been shown to require the GEF function of GIV to transduce downstream signaling. Solid lines connecting the receptor (i.e. RTK) to GIV represent direct coupling by physical interaction, whereas the dotted lines represent coupling by an unknown mechanism. InsR, insulin receptor; PDGFR, PDGF receptor; VEGFR, VEGF receptor; fMLPR, formylmethionylleucylphenylalanine receptor; LPAR, lysophosphatidic acid receptor; TGFβR, transforming growth factor β receptor; mTOR, mammalian target of rapamycin; pCREB, phosphorylated CREB; pTyr, phosphotyrosine. Bottom, summary of different signaling pathways that are either enhanced (green upward arrow) or suppressed (red downward arrow) by the GEF activity of GIV. Numbers indicate the reference number in the text for the publication where the original finding was reported.
FIGURE 3.
FIGURE 3.
GIV directly binds multiple ligand-activated RTKs via an SH2-like domain in its C terminus. Top, a schematic summarizing the sequence of events triggered by growth factors (such as EGF) is shown. Upon ligand stimulation, RTK dimerization and autophosphorylation of the cytoplasmic tail are triggered. Specific phosphotyrosines within the RTK tail (e.g. Tyr-1148 and Tyr-1173 on EGFR) serve as sites for the recruitment of GIV. Such recruitment requires recognition of phosphotyrosine ligands by an ∼110-aa stretch within the C terminus of GIV that folds into an SH2-like domain that stably docks onto autophosphorylated RTK tail. Close proximity to EGFR facilitates efficient phosphorylation of GIV on critical tyrosines that bind and activate Class 1 PI3-kinases. InsR, insulin receptor; PDGFR, PDGF receptor; VEGFR, VEGF receptor. Bottom, molecular modeling of the interface between the SH2 domain of GIV (red, white, and blue) and EGFR-derived phosphotyrosine peptide (purple) corresponding to Tyr(P)-1148 and its flanking residues, a high-affinity binding site for GIV on the EGF receptor. The acidic, neutral, and basic potentials are displayed in red, white, and blue, respectively. The electrostatic surface potential of the phosphotyrosine recognition and binding pocket of the SH2 domain of GIV is mostly basic. GIV CT, GIV C terminus.
FIGURE 4.
FIGURE 4.
The GEF up-regulation of GIV is directly linked to multiple human diseases. A model depicting the common theme for the role of GIV in disease (from top to bottom) is shown. Up-regulation of GIV expression promotes its coupling to G proteins and enhancement of downstream signaling events. This altered pattern of signaling triggers phenotypic changes in key cell types, thereby contributing to disease progression. Examples of this mechanism of the action of GIV have been described in hepatic stellate cells during liver fibrosis (47), tumor cells during metastatic progression (30, 32, 36, 58), and kidney podocytes upon nephrotic injury (48).
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