Src Homology Domain 2-containing Protein-tyrosine Phosphatase-1 (SHP-1) Binds and Dephosphorylates Gα-interacting, Vesicle-associated Protein (GIV)/Girdin and Attenuates the GIV-Phosphatidylinositol 3-Kinase (PI3K)-Akt Signaling Pathway

Mittal, Yash; Pavlova, Yelena; Garcia‐Marcos, Mikel; Ghosh, Pradipta

doi:10.1074/jbc.m111.275685

Cited by 35 publications

(34 citation statements)

References 65 publications

(92 reference statements)

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“…Despite this, it is hypothesized that the role of girdin in ESCCs is possibly through its binding proteins, including actin, Akt and heterotrimeric G proteins (20)(21)(22)(23). Actin is the major ingredient in the cellular cytoskeleton and the dynamic reorganization of the cell cytoskeleton controls cellular motility (24,25).…”

Section: Rr 95% CI -----------------------------------------mentioning

confidence: 99%

Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells

Cao

Jiang

Cao

et al. 2014

Molecular Medicine Reports

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Girdin is an actin-binding Akt substrate that is involved in the regulation of cell migration. Accumulating evidence has revealed that girdin has regulatory effects on invasion and metastasis in several types of cancer. However, the role of girdin in esophageal squamous cell carcinomas (ESCCs) is yet to be investigated. In the present study, tissue microarray data revealed that among 95 cases of ESCC, 27 cases (28.7%) exhibited a low expression of girdin, while 67 cases (71.3%) had an enhanced expression of girdin. However, among 78 cases of adjacent tissues, 64 cases (82.1%) did not express girdin and 14 cases (17.9%) exhibited a low expression of girdin. Furthermore, the expression of girdin was significantly associated with the tumor stage, lymph node metastasis stage, and tumor, lymph node and metastasis stage. Of note, the mean survival time of girdin-positive cases was only 30.62±2.99 months, while it was 53.37±5.02 months in girdin-negative cases, indicating that girdin protein expression is an independent prognostic factor of poor survival. Talen-mediated girdin knockout (KO) significantly suppressed cellular proliferation, migration and invasion in ESCC ECA109 cells. In conclusion, the present study suggested that girdin protein expression was significantly correlated with cancer progression and poor prognosis in ESCCs, and that girdin had a positive role in the regulation of cell proliferation, migration and invasion in ESCC cells. Therefore, girdin may be a potential candidate for the development of novel prognostic tools and therapeutic strategies for ESCCs.

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Section: Rr 95% CI -----------------------------------------mentioning

confidence: 99%

Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells

Cao

Jiang

Cao

et al. 2014

Molecular Medicine Reports

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“…In the case of the PI3K-Akt signaling pathway, GIV enhances it by two synergistic but independent mechanisms: (i) activation of Gαi via GIV's GEF motif releases free Gβγ subunits that bind and activate class 1B PI3-kinases (1,3,4,6) and (ii) phosphorylation of GIV by multiple RTKs and non-RTKs at tyrosines 1764 and 1798 that directly bind and activate class 1A PI3-kinases (11). The latter is down-regulated by SH2 domain-containing tyrosine phoaphatase-1 (SHP-1), a protein tyrosine phosphatase that dephosphorylates GIV (26). Here we demonstrate that inhibitory phosphorylation of GIV's GEF motif by PKCθ at Ser 1689 establishes another negative feedback loop that down-regulates the receptor-GIV-PI3K (class PM (2, 7), where GIV's GEF motif activates Gi and releases free Gβγ subunits, which in turn activate Akt via class 1 PI3Ks (6).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C-theta (PKCθ) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin

López-Sánchez¹,

Garcia‐Marcos

Mittal³

et al. 2013

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

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Gα-interacting, vesicle-associated protein (GIV/Girdin) is a multidomain signal transducer that enhances PI3K-Akt signals downstream of both G-protein–coupled receptors and growth factor receptor tyrosine kinases during diverse biological processes and cancer metastasis. Mechanistically, GIV serves as a non-receptor guanine nucleotide exchange factor (GEF) that enhances PI3K signals by activating trimeric G proteins, Gαi1/2/3. Site-directed mutations in GIV’s GEF motif disrupt its ability to bind or activate Gi and abrogate PI3K-Akt signals; however, nothing is known about how GIV’s GEF function is regulated. Here we report that PKCθ, a novel protein kinase C, down-regulates GIV’s GEF function by phosphorylating Ser(S)1689 located within GIV’s GEF motif. We demonstrate that PKCθ specifically binds and phosphorylates GIV at S1689, and this phosphoevent abolishes GIV’s ability to bind and activate Gαi. HeLa cells stably expressing the phosphomimetic mutant of GIV, GIV-S1689→D, are phenotypically identical to those expressing the GEF-deficient F1685A mutant: Actin stress fibers are decreased and cell migration is inhibited whereas cell proliferation is triggered, and Akt (a.k.a. protein kinase B, PKB) activation is impaired downstream of both the lysophosphatidic acid receptor, a G-protein–coupled receptor, and the insulin receptor, a receptor tyrosine kinase. These findings indicate that phosphorylation of GIV by PKCθ inhibits GIV's GEF function and generates a unique negative feedback loop for downregulating the GIV-Gi axis of prometastatic signaling downstream of multiple ligand-activated receptors. This phosphoevent constitutes the only regulatory pathway described for terminating signaling by any of the growing family of nonreceptor GEFs that modulate G-protein activity.

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“…These confluent cultures were subjected to high density scratch wounding using a sterilized, metal, 250-toothed wounding comb exactly as we have done previously (2,3,14,(23)(24)(25).…”

Section: Methodsmentioning

confidence: 99%

“…Equal amounts of total cellular proteins were separated by 10% SDS-PAGE and transferred to PVDF membranes (Millipore, Billerica, MA). Immunoblotting and quantification were carried out as described previously (25) by dual color infrared imaging using an Odyssey imaging system (LI-COR Biosciences). All individual images were processed with ImageJ software (National Institutes of Health) and assembled for presentation with Photoshop and Illustrator software (both Adobe).…”

Section: Methodsmentioning

confidence: 99%

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

Ong

Notani

et al. 2012

Journal of Biological Chemistry

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Src Homology Domain 2-containing Protein-tyrosine Phosphatase-1 (SHP-1) Binds and Dephosphorylates Gα-interacting, Vesicle-associated Protein (GIV)/Girdin and Attenuates the GIV-Phosphatidylinositol 3-Kinase (PI3K)-Akt Signaling Pathway

Cited by 35 publications

References 65 publications

Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells

Talen-mediated girdin knockout downregulates cell proliferation, migration and invasion in human esophageal carcinoma ECA109 cells

Protein kinase C-theta (PKCθ) phosphorylates and inhibits the guanine exchange factor, GIV/Girdin

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

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