Cortical beta-catenin and APC regulate asymmetric nuclear beta-catenin localization during asymmetric cell division in C. elegans

In C. elegans, Wnt signaling regulates a number of asymmetric cell divisions. During telophase, WRM-1/beta-catenin localizes asymmetrically to the anterior cortex and the posterior daughter's nucleus. However, cortical WRM-1's functions are not known. Here, we use a membrane-targeted form of WRM-1 to show that cortical WRM-1 inhibits Wnt signaling and the nuclear localization of WRM-1. These functions are mediated by APR-1/APC, which regulates WRM-1 nuclear export. We also show that APR-1 as well as PRY-1/Axin and Dishevelled homologs localize asymmetrically to the cortex. Our results suggest a model in which cortical WRM-1 recruits APR-1 to the anterior cortex before and during division, and the cortical APR-1 stimulates WRM-1 export from the anterior nucleus at telophase. Because beta-catenin and APC are localized to the cortex in many cell types in different species, our results suggest that these cortical proteins may regulate asymmetric divisions or Wnt signaling in other organisms as well.     

When timing is everything: role of cell cycle regulation in asymmetric division

Asymmetric division is a fundamental mechanism of generating cell diversity during development. One of its hallmarks is asymmetric localization during mitosis of proteins that specify daughter cell fate. Studies in Drosophila show that subcellular localization of many proteins required for asymmetric division of neuronal progenitors correlates with progression through mitosis. Yet, how cell cycle and asymmetric division machineries cooperate remains unclear. Recent data show that (1) key cell cycle regulators are required for asymmetric localization of cell fate determinants and for cell fate determination and (2) molecules that mediate asymmetric division can also act to modulate proliferation potential of progenitor cells.     

Novel findings on actin regulation in asymmetric division of mouse oocytes

Comment on: Sun SC, et al. Cell Cycle 2011; 10:1853-60.     

Stem cell self-renewal: The role of asymmetric division

Asymmetric division occurs widely in different groups of organisms from single-celled to insects, mammals, and plants. The operation of asymmetrical division may differ widely in different organisms. In multicellular organisms, asymmetrical division is one of the essential features of stem cell biology. The data obtained assume one of the main biological functions of asymmetrical division to be maintenance of cell viability, beginning with stem cells. Cells continuously accumulate toxic inclusions, which are formed by damaged proteins which cannot be degraded by proteasomes. As a result of asymmetric division, these inclusions segregate into one of the daughter cells providing the ability of long-lived proliferation to another cell.     

Mechanisms of asymmetric stem cell division

Stem cells self-renew but also give rise to daughter cells that are committed to lineage-specific differentiation. To achieve this remarkable task, they can undergo an intrinsically asymmetric cell division whereby they segregate cell fate determinants into only one of the two daughter cells. Alternatively, they can orient their division plane so that only one of the two daughter cells maintains contact with the niche and stem cell identity. These distinct pathways have been elucidated mostly in Drosophila. Although the molecules involved are highly conserved in vertebrates, the way they act is tissue specific and sometimes very different from invertebrates.     

Phosphorylation and regulation of beta-catenin by casein kinase I epsilon

beta-Catenin transduces cytosolic signals to the nucleus in the Wnt pathway. The Wnt ligand stabilizes cytosolic beta-catenin protein, preventing its phosphorylation by inhibiting glycogen synthase kinase 3 (GSK3). Serine-33 and -37 of beta-catenin are GSK3 phosphorylation sites that serve as recognition sites for the beta-TRCP-ubiquitin ligase complex, which ultimately triggers beta-catenin degradation. Mutations at those two sites, as well as in Ser-45, stabilize beta-catenin. Recently, casein kinase I epsilon (CKI epsilon) has been shown to be a positive regulator of the Wnt pathway. Its action mechanism, however, remains unknown. Here I show that Ser-45 is phosphorylated not by GSK3 but by CKI epsilon. Axin, a scaffold protein that binds CKI epsilon and beta-catenin, enhances this CKI epsilon-mediated phosphorylation. Overexpression of CKI epsilon in cells increases the amount of beta-catenin phosphorylated at Ser-45. Ser-45 phosphorylated beta-catenin is a better substrate for GSK3, which suggests that CKI epsilon and GSK3 may co-operate in destabilizing beta-catenin. In spite of the fact that CKI epsilon was found as a positive regulator of the Wnt pathway, mutational analysis suggests that mutation of Ser-45 regulates beta-catenin stability by inhibiting the ability of GSK3 to phosphorylate Ser-33 and -37, thereby disrupting the interaction between beta-catenin, beta-TRCP and Axin. I propose that phosphorylation of Ser-45 by CKI epsilon plays an important role in regulating beta-catenin stability.     

TB or not TB: calcium regulation in mycobacterial survival

Mycobacterium tuberculosis (Mtb)-the bacterium that causes tuberculosis-resides in phagosomes inside macrophages. This bacterium evades destruction by preventing phagosome maturation, which involves the fusion of phagosomes with lysosomes. In this issue of Cell, Jayachandran et al. (2007) suggest that mycobacteria co-opt the actin-binding protein coronin 1 to activate the phosphatase calcineurin, thereby preventing phagosomal maturation.     

GM130: New insights into oocyte asymmetric division

Comment on: Zhang CH, et al. Cell Cycle 2011; 10:1639-54.     

Embryonic polarity: protein stability in asymmetric cell division

Recent work on pattern formation in Caenorhabditis elegans has uncovered a new mechanism of asymmetric cell division: the cytoplasm is polarized by cortical proteins, and this polarization then influences the stability of other maternally expressed proteins that in turn determine early embryonic cell fates.     

Multiple levels of regulation specify the polarity of an asymmetric cell division in C. elegans

Wnt signaling systems play important roles in the generation of cell and tissue polarity during development. We describe a Wnt signaling system that acts in a new way to orient the polarity of an epidermal cell division in C. elegans. In this system, the EGL-20/Wnt signal acts in a permissive fashion to polarize the asymmetric division of a cell called V5. EGL-20 regulates this polarization by counteracting lateral signals from neighboring cells that would otherwise reverse the polarity of the V5 cell division. Our findings indicate that this lateral signaling pathway also involves Wnt pathway components. Overexpression of EGL-20 disrupts both the asymmetry and polarity of lateral epidermal cell divisions all along the anteroposterior (A/P) body axis. Together our findings suggest that multiple, inter-related Wnt signaling systems may act together to polarize asymmetric cell divisions in this tissue.     

Polarization and asymmetric division of stem cells

Asymmetric cell division observed in many groups of organisms has similar mechanisms suggesting conservatism of the process. Asymmetric division of stem cells that reside in their niches is aimed to regulation of cell proliferation and genome stability maintenance. But stem cells may also divide symmetrically depending on situation. Alteration of mechanisms of asymmetric division might be one of the factors of neoplasm growth.     

Wnt/beta-catenin signaling down-regulates N-acetylglucosaminyltransferase III expression: the implications of two mutually exclusive pathways for regulation

In previous studies, we reported that N-acetylglucosaminyltransferase III (GnT-III) activity and the enzyme product, bisected N-glycans, both were induced in cells cultured under dense conditions in an E-cadherin-dependent manner (Iijima, J., Zhao, Y., Isaji, T., Kameyama, A., Nakaya, S., Wang, X., Ihara, H., Cheng, X., Nakagawa, T., Miyoshi, E., Kondo, A., Narimatsu, H., Taniguchi, N., and Gu, J. (2006) J. Biol. Chem. 281, 13038-13046). Furthermore, we found that α-catenin, a component of the E-cadherin-catenin complex, was also required for this induction (Akama, R., Sato, Y., Kariya, Y., Isaji, T., Fukuda, T., Lu, L., Taniguchi, N., Ozawa, M., and Gu, J. (2008) Proteomics 8, 3221-3228). To further explore the molecular mechanism of this regulation, the roles of β-catenin, an essential molecule in both cadherin-mediated cell adhesion and canonical Wnt signaling, were investigated. Unexpectedly, shRNA knockdown of β-catenin resulted in a dramatic increase in GnT-III expression and its product, the bisected N-glycans, which was confirmed by RT-PCR and GnT-III activity and by E4-PHA lectin blot analysis. The induction of GnT-III expression increased bisecting GlcNAc residues on β1 integrin, which led to down-regulation of integrin-mediated cell adhesion and cell migration. Immunostaining showed that nuclear localization of β-catenin was greatly suppressed; intriguingly, the knockdown of β-catenin in the nuclei was more effective than that in cell-cell contacts in the knockdown cells, which was also confirmed by Western blot analysis. Stimulation of the Wnt signaling pathway by the addition of exogenous Wnt3a or BIO, a GSK-3β inhibitor, consistently and significantly inhibited GnT-III expression and its products. Conversely, the inhibition of β-catenin translocation into the nuclei increased GnT-III activation. Taken together, the results of the present study are the first to clearly demonstrate that GnT-III expression may be precisely regulated by the interplay of E-cadherin-catenin complex-mediated cell-cell adhesion and Wnt/β-catenin signaling, which are both crucial in the process of epithelial-mesenchymal transitions in physiological and pathological conditions.