G protein coupled growth factor receptor tyrosine kinase:<i>no longer an oxymoron</i>

Ghosh, Pradipta

doi:10.1080/15384101.2015.1066538

Cited by 18 publications

(22 citation statements)

References 37 publications

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“…Thus GIV is ubiquitously expressed (10), can be recruited to different subcellular compartments (reviewed in ref. 4), binds to both Gαi and Gαs (9)(10)(11), and affects a number of important physiologic and pathologic processes.…”

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confidence: 99%

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

Gupta

Bhandari

Leyme

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.

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confidence: 99%

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

Gupta

Bhandari

Leyme

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…1‐4). Among the numerous pathways that GIV affects are the prometastatic PI3K‐Akt and STAT3 signaling pathways (2, 4, 5). Mechanistically, GIV modulates multireceptor signaling via its fundamental ability to serve as a guanine exchange factor (GEF) for the heterotrimeric (henceforth trimeric) G protein, Gai.…”

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confidence: 99%

“…Consistent with its ability to serve as a central hub for modulation of multireceptor/pathway signaling, GIV is involved in a wide range of biologic processes such as cancer cell migration, tumor angiogenesis, tumor-stroma interaction during cancer progression, cancer invasion, epithelial wound healing, organ fibrosis, neuronal migration, memory formation, macrophage chemotaxis, and vascular repair (2,4,(8)(9)(10)(11). The finding that GIV and its GEF function are essential for signal enhancement (such as PI3K-Akt) and actin remodeling during cancer cell migration and invasion in vitro (10,12) led to the discoveries that GIV is essential for tumor invasion and metastasis in murine models (12)(13)(14)(15)(16)(17).…”

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confidence: 99%

Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers

et al. 2016

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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.

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“…But unlike any other modulator of G proteins, GIV has a unique modular makeup (see Fig 1, top ) that allows it to couple to diverse classes of ligand-activated receptors, such as growth factor receptor tyrosine kinases (RTKs), G protein coupled receptors (GPCRs), integrins, toll-like receptors, and the family of TGF-β receptors, many of which are believed to relay signals exclusively via tyrosine-based signals. Published work has revealed that such coupling allows diverse types of stimuli to activate Gαi proteins via GIV, and has established a non-canonical mechanism for convergent and coordinated G protein signaling [reviewed in ( Ghosh, 2015a ; Ghosh, 2015c ; Ghosh, 2016 )]. The unique combination of modules and motifs in GIV (see Fig 1, top ) which enables it to receive tyrosine-based signal inputs and relay them via G protein intermediates, positioning GIV at the intersection of two of the largest signaling hubs in eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

“…[reviewed in ( Aznar et al, 2016b ; Ghosh, 2015c ; Ghosh, 2016 )], thus making it an interesting target for fundamental as well as translational studies. These studies have not only revealed GIV's pathophysiologic importance ( Ghosh, 2016 ), but also its diagnostic and therapeutic potential in a variety of disease states [reviewed in ( Aznar et al, 2016b ; Ghosh, 2015a ; Ghosh, 2015c )].…”

Section: Introductionmentioning

confidence: 99%

Biochemical, Biophysical and Cellular Techniques to Study the Guanine Nucleotide Exchange Factor, GIV/Girdin

Ghosh

Aznar

Swanson

et al. 2016

CP Chemical Biology

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Canonical signal transduction via heterotrimeric G proteins is spatiotemporally restricted, i.e. triggered exclusively at the plasma membrane, only by agonist activation of G protein-coupled receptors via a finite process that is terminated within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a non-canonical pathway for activation of heterotrimeric G proteins via the non-receptor guanidine-nucleotide exchange factor, GIV/Girdin. Biochemical, biophysical and functional studies evaluating this pathway have unraveled its unique properties and distinctive spatiotemporal features. As in the case of any new pathway/paradigm, these studies first required an in-depth optimization of tools/techniques and protocols, governed by rationale and fundamentals unique to the pathway, and more specifically to the large multimodular GIV protein. Here we provide the most up-to-date overview of protocols that have generated most of what we know today about non-canonical G protein activation by GIV and its relevance in health and disease.

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G protein coupled growth factor receptor tyrosine kinase:no longer an oxymoron

Cited by 18 publications

References 37 publications

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

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

Prognostic impact of total and tyrosine phosphorylated GIV/Girdin in breast cancers

Biochemical, Biophysical and Cellular Techniques to Study the Guanine Nucleotide Exchange Factor, GIV/Girdin

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