Regulation and Physiological Functions of G12/13-Mediated Signaling Pathways

Suzuki, Naomichi; Hajicek, Nicole; Kozasa, Tohru

doi:10.1159/000186690

Cited by 102 publications

(86 citation statements)

References 145 publications

(207 reference statements)

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“…Ga 13 signaling is required for myocardial migration S1pr2 has been shown to couple with diverse G proteins, in particular Ga 12 and Ga 13 , to mediate a variety of cellular responses (Skoura and Hla, 2009;Suzuki et al, 2009). We previously identified one Ga 12 and two Ga 13 (Ga 13 a and Ga 13 b) isoforms in zebrafish, and demonstrated that they are essential during gastrulation (Lin et al, 2005;Lin et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

“…S1pr2/Ga 13 signaling regulates myocardial migration via a RhoGEF/Rho-dependent pathway Next, we investigated the molecular effectors of S1pr2/Ga 13 -regulated myocardial migration. Ga 12 and Ga 13 function primarily by activating RhoGEF and then RhoA (Suzuki et al, 2009). We have previously shown that Ga 13 a binds a PDZRhoGEF known as Arhgef11, via its regulator of G protein-coupled signaling (RGS) domain, and that Ga 12/13 regulate zebrafish epiboly through a RhoGEF-dependent pathway.…”

Section: Research Articlementioning

confidence: 99%

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S1pr2/Gα13 signaling controls myocardial migration by regulating endoderm convergence

Lin

2013

Development

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SUMMARYA key process during vertebrate heart development is the migration of bilateral populations of myocardial precursors towards the midline to form the primitive heart tube. In zebrafish, signaling mediated by sphingosine-1-phosphate (S1P) and its cognate G proteincoupled receptor (S1pr2/Mil) is essential for myocardial migration, but the underlying mechanisms remain undefined. Here, we show that suppression of Ga 13 signaling disrupts myocardial migration, leading to the formation of two bilaterally located hearts (cardia bifida). Genetic studies indicate that Ga 13 acts downstream of S1pr2 to regulate myocardial migration through a RhoGEF-dependent pathway. Furthermore, disrupting any component of the S1pr2/Ga 13 /RhoGEF pathway impairs endoderm convergence during segmentation, and the endodermal defects correlate with the extent of cardia bifida. Moreover, endoderm transplantation reveals that the presence of wild-type anterior endodermal cells in Ga 13 -deficient embryos is sufficient to rescue the endoderm convergence defect and cardia bifida, and, conversely, that the presence of anterior endodermal cells defective for S1pr2 or Ga 13 in wild-type embryos causes such defects. Thus, S1pr2/Ga 13 signaling probably acts in the endoderm to regulate myocardial migration. In support of this notion, cardiac-specific expression of Ga 13 fails to rescue cardia bifida in the context of global Ga 13 inhibition. Our data demonstrate for the first time that the Ga 13 /RhoGEF-dependent pathway functions downstream of S1pr2 to regulate convergent movement of the endoderm, an event that is crucial for coordinating myocardial migration.

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Section: Resultsmentioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

S1pr2/Gα13 signaling controls myocardial migration by regulating endoderm convergence

Lin

2013

Development

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“…Tyrosine phosphorylation is a commonly used mechanism for the regulation of RhoGEF activity and increased tyrosine phosphorylation following receptor activation has been reported for the three RGS-RhoGEFs family members (Chikumi et al, 2002;Guilluy et al, 2010;Suzuki et al, 2009;Suzuki et al, 2003). We treated MCF7-CXCR4 cells with CXCL12 and used a phosphotyrosine (PY)-specific antibody to immunoprecipitate PY-proteins (Fig.…”

Section: Stimulation Of Cxcr4 Leads To Tyrosine Phosphorylation Of Lsmentioning

confidence: 99%

“…To determine whether LSC or PRG was required for cell migration following stimulation of CXCR4, we used siRNA to selectively target LSC, LARG or PRG expression and assessed the effect on cell migration (Suzuki et al, 2009;Tesmer, 2009). Each siRNA reduced expression of its target gene by 90% or greater, without altering the expression of other RGS-RhoGEF proteins (Fig.…”

Section: Knockdown Of Prg Expression Profoundly Inhibits Cxcr4-mediatmentioning

confidence: 99%

PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA

Struckhoff

Rana

Kher

et al. 2013

Journal of Cell Science

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SummaryThe CXCL12-CXCR4 chemokine signaling pathway is a well-established driver of cancer progression. One key process promoted by CXCR4 stimulation is tumor cell motility; however, the specific signaling pathways leading to migration remain poorly understood. Previously, we have shown that CXCL12 stimulation of migration depends on temporal regulation of RhoA. However, the specific RhoGEF that translates CXCR4 signaling into RhoA activity and cell motility is unknown. We screened the three regulator of Gprotein signaling RhoGEFs (LSC, LARG and PRG) and found that PRG selectively regulated the migration and invasion of CXCR4-overexpressing breast tumor cells. Interestingly, we found that PDZ-RhoGEF (PRG) was required for spatial organization of F-actin structures in the center, but not periphery of the cells. The effects on the cytoskeleton were mirrored by the spatial effects on RhoA activity that were dependent upon PRG. Loss of PRG also enhanced adherens junctions in the epithelial-like MCF7-CXCR4 cell line, and inhibited directional persistence and polarity in the more mesenchymal MDA-MB-231 cell line. Thus, PRG is essential for CXCR4-driven tumor cell migration through spatial regulation of RhoA and the subsequent organization of the cytoskeletal structures that support motility. Furthermore, immunohistochemical analysis of human breast tumor tissues shows a significant increase of PRG expression in the invasive areas of the tumors, suggesting that this RhoGEF is associated with breast tumor invasion in vivo.

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“…GTP binding and activation of four classes of G proteins lead to stimulation of complex intracellular signaling networks. These include stimulation of adenylyl cyclase and production of cyclic AMP (cAMP) by Gα s , repression of cAMP production but stimulation of Src tyrosine kinase by members of activated G i proteins, activation of phospholipase Cβ (PLCβ) and subsequent release of intracellular Ca 2+ by G q family, and RhoGEF activation by G 12/13 [2][3][4]. Numerous studies have focused on the function of G protein signaling in differentiated, post-mitotic cells.…”

Section: Gpcr Signalingmentioning

confidence: 99%

G protein signaling controls the differentiation of multiple cell lineages

Wang¹,

Wong²

2009

BioFactors

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G protein‐coupled receptors (GPCRs) detect a great diversity of extracellular stimuli ranging from hormonal peptides, chemokines, neurotransmitters, lipids, nucleotides, amino acids, biogenic amines to ions. G protein‐coupled pathways regulate a rich collection of biological processes involved in normal physiological function of the body as well as in pathological progression of diseases. In addition to their function in postmitotic steady‐state tissues, GPCRs have been implicated in the differentiation of stem cells and tissue specific progenitor cells during development. Examples of these include the functions of nucleotides and neuropeptides in neuronal differentiation and axon growth, chemokines in lymphocyte differentiation and activation, and other GPCR‐mediated processes in the differentiation of adipocytes, osteoblasts and smooth muscle cells. This review summarizes the recent advances in our understanding of the importance of GPCR‐linked signaling cascades in the differentiation of different cell lineages. © 2009 International Union of Biochemistry and Molecular Biology, Inc.

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Regulation and Physiological Functions of G12/13-Mediated Signaling Pathways

Cited by 102 publications

References 145 publications

S1pr2/Gα13 signaling controls myocardial migration by regulating endoderm convergence

S1pr2/Gα13 signaling controls myocardial migration by regulating endoderm convergence

PDZ-RhoGEF is essential for CXCR4-driven breast tumor cell motility through spatial regulation of RhoA

G protein signaling controls the differentiation of multiple cell lineages

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