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GIV/Girdin activates G?i and inhibits G?s via the same motif.

ABSTRACT: We previously showed that guanine nucleotide-binding (G) protein ? subunit (G?)-interacting vesicle-associated protein (GIV), a guanine-nucleotide exchange factor (GEF), transactivates G? activity-inhibiting polypeptide 1 (G?i) proteins in response to growth factors, such as EGF, using a short C-terminal motif. Subsequent work demonstrated that GIV also binds G?s and that inactive G?s 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, G?i and G?s, remained unknown. Here we report that GIV is a bifunctional modulator of G proteins; it serves as a guanine nucleotide dissociation inhibitor (GDI) for G?s using the same motif that allows it to serve as a GEF for G?i. Upon EGF stimulation, GIV modulates G?i and G?s sequentially: first, a key phosphomodification favors the assembly of GIV-G?i complexes and activates GIV's GEF function; then a second phosphomodification terminates GIV's GEF function, triggers the assembly of GIV-G?s complexes, and activates GIV's GDI function. By comparing WT and GIV mutants, we demonstrate that GIV inhibits G?s 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 G? proteins integrates downstream signals and cellular responses.

SUBMITTER: Gupta V

PROVIDER: S-EPMC5047194 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Gupta Vijay V Bhandari Deepali D Leyme Anthony A Aznar Nicolas N Midde Krishna K KK Lo I-Chung IC Ear Jason J Niesman Ingrid I López-Sánchez Inmaculada I Blanco-Canosa Juan Bautista JB von Zastrow Mark M Garcia-Marcos Mikel M Farquhar Marilyn G MG Ghosh Pradipta P

Proceedings of the National Academy of Sciences of the United States of America 20160912 39

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 mecha ...[more]

PMID: 27621449

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Project description:Gα-interacting vesicle-associated protein (GIV, aka Girdin) is a guanine exchange factor (GEF) for the trimeric G protein Gαi and a bona fide metastasis-related gene that serves as a platform for amplification of tyrosine-based signals via G-protein intermediates. Here we present the first exploratory biomarker study conducted on a cohort of 187 patients with breast cancer to evaluate the prognostic role of total GIV (tGIV) and tyrosine phosphorylated GIV (pYGIV) across the various molecular subtypes. A Kaplan-Meier analysis of recurrence-free survival showed that the presence of tGIV, either cytoplasmic or nuclear, carried poor prognosis, but that nuclear tGIV had a greater prognostic impact (P = 0.007 in early and P = 0.0048 in late clinical stages). Activated pYGIV in the cytoplasm had the greatest prognostic impact in late clinical stages (P = 0.006). Furthermore, we found that the prognostic impacts of cytoplasmic pYGIV and nuclear tGIV were additive (hazard ratio 19.0548; P = 0.0002). Surprisingly, this additive effect of nuclear tGIV/cytoplasmic pYGIV was observed in human epidermal growth factor receptor 2-positive tumors (hazard ratio 16.918; P = 0.0005) but not in triple-negative breast cancers. In triple-negative breast cancers, tGIV and cytoplasmic pYGIV had no prognostic impact; however, membrane-association of pYGIV carried a poor prognosis (P = 0.026). Both tGIV and pYGIV showed no correlation with clinical stage, tumor size, pathologic type, lymph node involvement, and BRCA1/2 status. We conclude that immunocytochemical detection of pYGIV and tGIV can serve as an effective prognosticator. On the basis of the differential prognostic impact of tGIV/pYGIV within each molecular subtype, we propose a diagnostic algorithm. Further studies on larger cohorts are essential to rigorously assess the effectiveness and robustness of this algorithm in prognosticating outcome among patients with breast cancer.-Dunkel, Y., Diao, K., Aznar, N., Swanson, L., Liu, L., Zhu, W., Mi, X.-Y., Ghosh, P. Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers.

Dataset Information

GIV/Girdin activates G?i and inhibits G?s via the same motif.

Publications

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

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