Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity

Smith, Travis K.; Hager, Hillary A.; Francis, Richard; Kilkenny, Dawn M.; Lo, Clive; Bader, David M.

doi:10.1073/pnas.0802345105

Cited by 64 publications

(91 citation statements)

References 58 publications

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“…a n for these characteristics does not add up to total studied (n ¼ 557) because of missing information. Cancer Researchp63RhoGEF, an important Gaq effector, has been reported to mediate RhoA, Rac1, or Cdc42 activation in different cell types (35,41,42). Our data showed that GPR116 mediated RhoA and Rac1 activation by Gaq and p63RhoGEF signaling.…”

Section: Discussionsupporting

confidence: 53%

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GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Tang

Jin

et al. 2013

Cancer Research

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Adhesion G-protein-coupled receptors (GPCR), which contain adhesion domains in their extracellular region, have been found to play important roles in cell adhesion, motility, embryonic development, and immune response. Because most adhesion molecules with adhesion domains have vital roles in cancer metastasis, we speculated that adhesion GPCRs are potentially involved in cancer metastasis. In this study, we identified GPR116 as a novel regulator of breast cancer metastasis through expression and functional screening of the adhesion GPCR family. We found that knockdown of GPR116 in highly metastatic (MDA-MB-231) breast cancer cells suppressed cell migration and invasion. Conversely, ectopic GPR116 expression in poorly metastatic (MCF-7 and Hs578T) cells promoted cell invasion. We further showed that knockdown of GPR116 inhibited breast cancer cell metastasis in two mammary tumor metastasis mouse models. Moreover, GPR116 modulated the formation of lamellipodia and actin stress fibers in cells in a RhoA-and Rac1-dependent manner. At a molecular level, GPR116 regulated cell motility and morphology through the Gaq-p63RhoGEF-RhoA/Rac1 pathway. The biologic significance of GPR116 in breast cancer is substantiated in human patient samples, where GPR116 expression is significantly correlated with breast tumor progression, recurrence, and poor prognosis. These findings show that GPR116 is crucial for the metastasis of breast cancer and support GPR116 as a potential prognostic marker and drug target against metastatic human breast cancer. Cancer Res; 73(20); 6206-18. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 53%

“…In addition, p63Rho-GEF/GEFT has been reported to activate Rac1 and mediate tumorigenesis, tumor metastasis, and myogenesis (8,35,36). To investigate whether p63RhoGEF is required for the activation of RhoA and Rac1 in breast cancer cells, we overexpressed p63RhoGEF in MDA-MB-231 cells.…”

Section: Regulation Of Rhoa and Rac1 Activity By Gpr116 Is Through P6mentioning

confidence: 99%

GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Tang

Jin

et al. 2013

Cancer Research

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“…Because uterine luminal epithelial transformation involves dynamic reorganization of the actin cytoskeleton, 28 and that Rac1 has been shown to be involved in orchestrating cell shape remodeling, 20,21,29 we speculated that uterine Rac1 deficiency would impair the functional integrity of the luminal epithelia at periimplantation. Indeed, electron microscopy analysis revealed a dramatic cell shape difference between the Claudin 7 was comparably expressed in the basolateral surface in both WT and Rac1 null epithelium, its prominent expression in the apical membrane of epithelial cells disappeared in the absence of uterine Rac1 (Figure 4g).…”

Section: Resultsmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

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“…Apart from ion channels and pumps, it is pos- sible that Popdc also interacts with proteins involved in channel oligomerization or membrane trafficking. VAMP2/3 and GEFT are 2 proteins that have been shown to interact with Popdc1 (47,48). VAMP2/3 has been shown to be involved in membrane vesicle fusion and could be involved in ion channel trafficking.…”

Section: Discussionmentioning

confidence: 99%

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

Froese

Breher²,

Waldeyer³

et al. 2012

J. Clin. Invest.

140

455

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Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention.

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Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity

Cited by 64 publications

References 58 publications

GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

GPR116, an Adhesion G-Protein–Coupled Receptor, Promotes Breast Cancer Metastasis via the Gαq-p63RhoGEF-Rho GTPase Pathway

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice

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