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Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin.

ABSTRACT: A role for Rac1 GTPase in canonical Wnt signaling has recently been demonstrated, showing that it is required for ?-catenin translocation to the nucleus. In this study, we investigated the mechanism of Rac1 stimulation by Wnt. Upregulation of Rac1 activity by Wnt3a temporally correlated with enhanced p120-catenin binding to Rac1 and Vav2. Vav2 and Rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by CK1 and inhibited by tyrosine phosphorylation by Src or Fyn. Acting on these two post-translational modifications, Wnt3a induced the release of p120-catenin from E-cadherin, enabled the interaction of p120-catenin with Vav2 and Rac1, and facilitated Rac1 activation by Vav2. Given that p120-catenin depletion disrupts gastrulation in Xenopus, we analyzed p120-catenin mutants for their ability to rescue this phenotype. In contrast to the wild-type protein or other controls, p120-catenin point mutants that were deficient in the release from E-cadherin or in Vav2 or Rac1 binding failed to rescue p120-catenin depletion. Collectively, these results indicate that binding of p120-catenin to Vav2 and Rac1 is required for the activation of this GTPase upon Wnt signaling.

SUBMITTER: Valls G

PROVIDER: S-EPMC3561852 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin.

Valls Gabriela G Codina Montserrat M Miller Rachel K RK Del Valle-Pérez Beatriz B Vinyoles Meritxell M Caelles Carme C McCrea Pierre D PD García de Herreros Antonio A Duñach Mireia M

Journal of cell science 20120903 Pt 22

A role for Rac1 GTPase in canonical Wnt signaling has recently been demonstrated, showing that it is required for β-catenin translocation to the nucleus. In this study, we investigated the mechanism of Rac1 stimulation by Wnt. Upregulation of Rac1 activity by Wnt3a temporally correlated with enhanced p120-catenin binding to Rac1 and Vav2. Vav2 and Rac1 association with p120-catenin was modulated by phosphorylation of this protein, which was stimulated upon serine/threonine phosphorylation by CK1 ...[more]

PMID: 22946057

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Project description:Estrogen levels decline in both sexes with age, but more dramatically in females. Activation of the Wnt/β-catenin signaling pathway is central to the regulation of bone mass accrual and maintenance and in response to mechanical loading. Using the ovariectomized mouse model we examined the effect of estrogen loss on the osteocyte's ability to activate the Wnt/β-catenin pathway following mechanical loading. Female TOPGAL mice underwent ovariectomy (OVX) (n = 10) or sham surgery (n = 10) at 16 weeks of age. Four weeks post-surgery, a single loading session (global strain of 2200 με for 100 cycles at 2 Hz) was performed on the right forearm with the left as a non-loaded control. Mice (n = 5) were sacrificed at 1 or 24 hr post-load. Ulnae were stained for β-catenin activation, femurs were used for μCT and 3-pt bending/biomechanical testing, and tibiae were used for histology analysis and to determine osteocyte lacunar size using SEM and high resolution micro-XCT. A 2.2-fold increase in β-catenin signaling activation was observed 24 hr post-load in the Sham group but did not occur in the OVX group. The OVX group versus control had significant losses (p < 0.05) in trabecular BMD (-8%), BV/TV (-35%) and thickness (-23%), along with cortical thickness (-6%) and periosteal perimeter (-4%). The OVX group had significantly higher trabecular bone osteoclast numbers (63%), OCS/BS (77%) and N.OC/BPm (94%) and a significant decrease in osteoblast number (53%), OBS/BS (37%) and N.OB/BPm (40%) compared to the sham group (p < 0.05). Cortical bone lacunar number/lacunar volume and bone biomechanical properties did not change between groups. Given that the ulna is a cortical bone loading model and the lack of changes in osteocyte lacunar number/volume in cortical bone, which would alter strains experienced by osteocytes, these data suggest the absence of estrogen resulted in intrinsic changes in the ability of the osteocyte to respond to mechanical load, rather than changes in the biomechanical and architectural properties of bone.

Dataset Information

Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin.

Publications

Upon Wnt stimulation, Rac1 activation requires Rac1 and Vav2 binding to p120-catenin.

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