Wnt signaling pathways meet Rho GTPases

Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Genes & development (Impact Factor: 10.8). 03/2009; 23(3):265-77. DOI: 10.1101/gad.1760809
Source: PubMed


Wnt ligands and their receptors orchestrate many essential cellular and physiological processes. During development they control differentiation, proliferation, migration, and patterning, while in the adult, they regulate tissue homeostasis, primarily through their effects on stem cell proliferation and differentiation. Underpinning these diverse biological activities is a complex set of intracellular signaling pathways that are still poorly understood. Rho GTPases have emerged as key mediators of Wnt signals, most notably in the noncanonical pathways that involve polarized cell shape changes and migrations, but also more recently in the canonical pathway leading to beta-catenin-dependent transcription. It appears that Rho GTPases integrate Wnt-induced signals spatially and temporally to promote morphological and transcriptional changes affecting cell behavior.

Download full-text


Available from: Nicholas S Tolwinski
  • Source
    • "In Caenorhabditis elegans early embryogenesis, a flow of cortical myosin and F-actin towards the anterior pole carries PAR polarity proteins, which in turn modulate the actomyosin dynamics (Munro et al., 2004; Mayer et al., 2010). Emerging evidence also point to a role for the Wnt/planar cell polarity (PCP) pathway in modulating cytoskeleton dynamics through its key mediators, Rho GTPases, which exert effects on actin polymerization and myosin contractility (Schlessinger et al., 2009), although the mechanisms underlying this cross-talk remain obscure. On the other hand, in vitro experiments on reconstituted cytoskeletal structures (Surrey et al., 2001), as well as recent mathematical models (Kruse et al., 2005; Hannezo et al., 2015) suggest that actomyosin gels could have the properties to self-assemble, but the applicability of these findings to in vivo situations is not yet clear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The actomyosin cytoskeleton is a primary force-generating mechanism in morphogenesis, thus a robust spatial control of cytoskeletal positioning is essential. In this report, we demonstrate that actomyosin contractility and planar cell polarity (PCP) interact in post-mitotic Ciona notochord cells to self-assemble and reposition actomyosin rings, which play an essential role for cell elongation. Intriguingly, rings always form at the cells' anterior edge before migrating towards the center as contractility increases, reflecting a novel dynamical property of the cortex. Our drug and genetic manipulations uncover a tug-of-war between contractility, which localizes cortical flows toward the equator and PCP, which tries to reposition them. We develop a simple model of the physical forces underlying this tug-of-war, which quantitatively reproduces our results. We thus propose a quantitative framework for dissecting the relative contribution of contractility and PCP to the self-assembly and repositioning of cytoskeletal structures, which should be applicable to other morphogenetic events.
    Full-text · Article · Oct 2015 · eLife Sciences
    • "These results provide compelling evidence that Ga 12/13 are bone fide mediators of alternative Wnt signaling, leading to YAP/TAZ activation. The Rho GTPase family is the major effector of Ga 12/13 signaling, and also plays a critical role in both alternative Wnt signaling and Hippo-YAP/TAZ regulation (Schlessinger et al., 2009; Yu et al., 2012; Zhao et al., 2012). C3 transferase, a specific RhoA inhibitor, significantly blocked Wnt3a-induced YAP/ TAZ activation in L-Wnt3a cells (Figure 1F). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcriptional co-activators YAP and TAZ are key regulators of organ size and tissue homeostasis, and their dysregulation contributes to human cancer. Here, we discover YAP/TAZ as bona fide downstream effectors of the alternative Wnt signaling pathway. Wnt5a/b and Wnt3a induce YAP/TAZ activation independent of canonical Wnt/β-catenin signaling. Mechanistically, we delineate the "alternative Wnt-YAP/TAZ signaling axis" that consists of Wnt-FZD/ROR-Gα12/13-Rho GTPases-Lats1/2 to promote YAP/TAZ activation and TEAD-mediated transcription. YAP/TAZ mediate the biological functions of alternative Wnt signaling, including gene expression, osteogenic differentiation, cell migration, and antagonism of Wnt/β-catenin signaling. Together, our work establishes YAP/TAZ as critical mediators of alternative Wnt signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Aug 2015 · Cell
  • Source
    • "The results are consistent with an earlier report of disrupted apicobasal polarity in Prickle1 mutant embryonic epiblasts (Tao et al., 2009). Actin assembly is a downstream event of PCP, which involves small GTPases (Schlessinger et al., 2009). We found that, rather than apical enrichment, the actin distribution was shifted more laterally in the mutant ureteric buds (Fig. 6E). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Planar cell polarity (PCP) signaling plays a critical role in tissue morphogenesis. In mammals, disruption of three of the six ‘‘core PCP’’ components results in polarity-dependent defects with rotated cochlear hair cell stereocilia and open neural tube. We recently demonstrated a role of Prickle1, a core PCP molecule in Drosophila, in mammalian neuronal development. To examine Prickle1function along a broader developmental window, we generated three mutant alleles in mice. We show that the complete loss of Prickle1 leads to systemic tissue outgrowth defects, aberrant cell organization and disruption of polarity machinery. Curiously, Prickle1 mutants recapitulate the characteristic features of human Robinow syndrome and phenocopy mouse mutants with Wnt5a or Ror2 gene defects, prompting us to explore an association of Prickle1 with the Wnt pathway. We show that Prickle1 is a proteasomal target of Wnt5a signaling and that Dvl2, a target of Wnt5a signaling, is misregulated in Prickle1 mutants. Our studies implicate Prickle1 as a key component of the Wnt-signaling pathway and suggest that Prickle1 mediates some of the WNT5A-associated genetic defects in Robinow syndrome
    Full-text · Article · Sep 2014 · Biology Open
Show more