STAT3 Protein Up-regulates Gα-interacting Vesicle-associated Protein (GIV)/Girdin Expression, and GIV Enhances STAT3 Activation in a Positive Feedback Loop during Wound Healing and Tumor Invasion/Metastasis

Dunkel, Ying; Ong, Andrew; Notani, Dimple; Mittal, Yash; Lam, Michael T.; Mi, Xiaoyi; Ghosh, Pradipta

doi:10.1074/jbc.m112.390781

Cited by 47 publications

(72 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We therefore investigated potential mechanisms of Girdin mRNA transcriptional regulation. The STAT3 transcription factor has recently been reported to activate Girdin transcription (Dunkel et al, 2012). However, PAR-3 silencing did not affect the levels of either STAT3 phosphorylated at Y705 or total STAT3 (supplementary material Fig.…”

Section: Ap-2 Regulates Girdin Transcriptionmentioning

confidence: 94%

“…However, how PAR-3 regulates the transcriptional activity of AP-2 remains to be established. The activation status of STAT3, another transcription factor involved in Girdin expression (Dunkel et al, 2012), was unaffected in PAR-3 kd cells. We predicted that PAR-3 located at cell-cell contact sites might activate unknown signaling cascade(s), resulting in AP-2 activation.…”

Section: Regulation Of Girdin Transcription By the Par-3 Cell Polaritmentioning

confidence: 97%

See 1 more Smart Citation

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Sasaki

Kakuwa

Akimoto

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

Epithelial apicobasal polarity has fundamental roles in epithelial physiology and morphogenesis. The PAR complex, comprising PAR-3, PAR-6 and aPKC, is involved in determining cell polarity in various biological contexts, including in epithelial cells. However, it is not fully understood how the PAR complex induces apicobasal polarity. In this study, we show that PAR-3 regulates the protein expression of Girdin (GIV/CCDC88A), a guanine nucleotide exchange factor (GEF) for heterotrimeric Gαi subunits, at the transcriptional level by cooperating with the AP-2 transcription factor. In addition, we confirmed that PAR-3 physically interacts with Girdin, and show that Girdin, together with the Gαi3, controls tight junction formation, apical domain development and actin organization downstream of PAR-3. Taken together, our findings suggest that transcriptional upregulation of Girdin and Girdin–Gαi3 signaling play crucial roles in regulating epithelial apicobasal polarity via the PAR complex.

show abstract

Section: Ap-2 Regulates Girdin Transcriptionmentioning

confidence: 94%

Section: Regulation Of Girdin Transcription By the Par-3 Cell Polaritmentioning

confidence: 97%

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Sasaki

Kakuwa

Akimoto

et al. 2015

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…First, wound healing is a multireceptor-driven process that involves coordination of diverse cell populations and cellular processes. Second, the ubiquitous expression of GIV in all cell types involved in healing, the transcriptional up-regulation of GIV after wounding, and the role GIV-GEF in many of those cells/processes has been well documented (7,8,11,13,14,17,18,22,35) (Fig. 4A).…”

Section: Cell-permeable Giv-ct-wt Peptides Accelerate Wound Healing Inmentioning

confidence: 99%

“…To analyze the effects of TAT-GIV-CT peptide on cells, we first optimized cellular uptake of these peptides in HeLa cells. We chose to study HeLa cells because this is a well accepted model system and has been extensively used to characterize the role of GIV in our prior work (16,18,29,30). Incubation of HeLa cells with 400-800 nM TAT-GIV-CT peptides for 30 min resulted in efficient uptake (∼90-100% cells by immunofluorescence) with no observed toxicity (Fig.…”

Section: Cell-permeable Giv-ct Peptides Are Effective In Exogenous Momentioning

confidence: 99%

“…It is because cells can alter (increase or decrease) the levels of GIV mRNA/protein or selectively modulate GIV's GEF activity to modulate growth factor signaling pathways across a range of intensities (16), we likened GIV to a cellular "rheostat" for signal transduction (17). Consistent with its ability to integrate signals downstream of multiple receptors, GIV modulates growth factor signaling during diverse biological processes (17), e.g., cell migration, chemotaxis (13), invasion (18), development (19), self-renewal (20), apoptosis (14,21), and autophagy (12). Increasing evidence also supports the clinical significance of GIV-dependent signaling during diverse disease processes (17), e.g., pathologic angiogenesis (11), liver fibrosis (14), nephrotic syndrome (21), vascular repair (22), and tumor metastasis (23).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

Gary

Aznar

Kalogriopoulos

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

In eukaryotes, receptor tyrosine kinases (RTKs) and trimeric G proteins are two major signaling hubs. Signal transduction via trimeric G proteins has long been believed to be triggered exclusively by G protein-coupled receptors (GPCRs). This paradigm has recently been challenged by several studies on a multimodular signal transducer, Gα-Interacting Vesicle associated protein (GIV/Girdin). We recently demonstrated that GIV’s C terminus (CT) serves as a platform for dynamic association of ligand-activated RTKs with Gαi, and for noncanonical transactivation of G proteins. However, exogenous manipulation of this platform has remained beyond reach. Here we developed cell-permeable GIV-CT peptides by fusing a TAT-peptide transduction domain (TAT-PTD) to the minimal modular elements of GIV that are necessary and sufficient for activation of Gi downstream of RTKs, and used them to engineer signaling networks and alter cell behavior. In the presence of an intact GEF motif, TAT-GIV-CT peptides enhanced diverse processes in which GIV’s GEF function has previously been implicated, e.g., 2D cell migration after scratch-wounding, invasion of cancer cells, and finally, myofibroblast activation and collagen production. Furthermore, topical application of TAT-GIV-CT peptides enhanced the complex, multireceptor-driven process of wound repair in mice in a GEF-dependent manner. Thus, TAT-GIV peptides provide a novel and versatile tool to manipulate Gαi activation downstream of growth factors in a diverse array of pathophysiologic conditions.

show abstract

Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time

et al. 2016

Self Cite

View full text Add to dashboard Cite

Canonical signal transduction via heterotrimeric G proteins is spatially and temporally restricted, i.e., triggered exclusively at the plasma membrane (PM), only by agonist activation of G-protein-coupled receptors (GPCRs) via a process that completes within a few hundred milliseconds. Recently, a rapidly emerging paradigm has revealed a non-canonical pathway for activation of trimeric G proteins by the non-receptor guanidine-nucleotide exchange factor (GEF), GIV/Girdin. This pathway has distinctive temporal and spatial features and an unusual profile of receptor engagement: Diverse classes of receptors, not just GPCRs can engage with GIV-GEF to trigger such activation. Such activation is spatially and temporally unrestricted, i.e., can occur both at the PM and on internal membranes discontinuous with the PM, and can continue for prolonged periods of time. Here we review the molecular mechanisms that govern non-canonical G protein activation by GIV-GEF and the relevance of this new paradigm in health and disease.

show abstract

STAT3 Protein Up-regulates Gα-interacting Vesicle-associated Protein (GIV)/Girdin Expression, and GIV Enhances STAT3 Activation in a Positive Feedback Loop during Wound Healing and Tumor Invasion/Metastasis

Cited by 47 publications

References 61 publications

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Regulation of epithelial cell polarity by PAR-3 depends on Girdin transcription and Girdin–Gαi3 signaling

Therapeutic effects of cell-permeant peptides that activate G proteins downstream of growth factors

Heterotrimeric G protein signaling via GIV/Girdin: Breaking the rules of engagement, space, and time

Contact Info

Product

Resources

About