Faculty / Research
Ken-Ichi Takemaru, Ph.D.Associate Professor
Ph.D., Graduate University for Advanced Studies, Japan
Postdoctoral, University of Washington
Cell Signaling and Ciliogenesis in Mammalian Development, Health and Disease
Wnt Signaling in Development and Disease
Intracellular signaling by the Wnt family of secreted cysteine-rich glycoproteins plays critical roles in embryonic development and adult homeostasis. This pathway is highly conserved among the animal kingdom. Importantly, perturbations of Wnt signaling have been linked to a range of human diseases. For instance, the best understood canonical Wnt/β-catenin pathway is aberrantly activated in greater than 70 % of colorectal cancers and to a lesser extent in other tumor types, promoting cancer cell proliferation, survival and migration. More recently, this signaling cascade has emerged as a crucial regulator of stem cells. Our laboratory investigates the function of Wnt signaling in the context of development and disease.
Chibby Family Members and Ciliogenesis
Cilia are ancient microtubule-based organelles that protrude from the apical cell surface to perform diverse biological functions, ranging from fluid movement to intracellular signaling. Dysfunctional cilia have been linked to various diseases, collectively known as ciliopathy. We previously reported a β-catenin-associated antagonist Chibby (Cby). Cby is a conserved shuttling protein that blocks transcriptional activation by β-catenin, a key coactivator downstream of canonical Wnt signaling. In our efforts to investigate the physiological function of Cby using Cby-knockout (Cby-/-) mice, we found that these mice suffer from chronic respiratory infections due to a complete absence of mucociliary transport activity. Our studies further uncovered that ciliated cells in the nasal and lung epithelia of Cby-/- mice are poorly differentiated characterized by markedly fewer ciliary projections. Consistent with this phenotype, endogenous Cby protein is highly enriched at the base of cilia, suggesting that Cby plays an essential role in proper formation/function of cilia. In mammals, there are three Cby homologues. Our current research is directed at understanding roles of Cby family members and Wnt/b-catenin signaling in ciliogenesis and ciliated cell differentiation.
Steere, N., Chae, V., Burke, M., Li, F.-Q., Takemaru, K.-I. & Kuriyama, R. (2012)
A Wnt/beta-catenin antagonist Chibby binds Cenexin at the distal end of mother centrioles and functions in primary cilia formation.
PLoS ONE, 7, e41077.
Kumamoto, N., Gu, Y., Wang, J., Janoschka, S., Takemaru, K.-I., Levine, J. & Ge, S. (2012)
A role for primary cilia in glutamatergic synaptic integration of adult-born neurons.
Nat. Neurosci., 15, 399-405.
Takemaru, K.-I., Chen, X. & Li, F.-Q. (2012)
Encyclopedia of Signaling Molecules, Springer.
Cyge, B., Fischer, V., Takemaru, K.-I. & Li, F.-Q. (2011)
Generation and characterization of monoclonal antibodies against human Chibby protein.
Hybridoma, 30, 163-168.
Love, D., Li, F.-Q., Burke, M.C., Cyge, B., Ohmitsu, M., Cabello, M., Larson, J.E., Brody, S.L., Cohen, J.C. & Takemaru, K.-I. (2010)
Altered lung morphogenesis, epithelial cell differentiation and mechanics in mice deficient in the Wnt/beta-catenin antagonist Chibby.
PLoS ONE, 5, e13600.
Li, F.-Q., Mofunanya, A., Fischer, V., Hall, J., & Takemaru, K.-I. (2010)
Nuclear-cytoplasmic shuttling of Chibby controls beta-catenin signaling.
Mol. Biol. Cell, 21:311-322.
Mofunanya, A., Li, F.-Q., Hsieh, J.-C., & Takemaru, K.-I. (2009)
Chibby forms a homodimer through a heptad repeat of leucine residues in its C-terminal coiled-coil motif.
BMC Mol. Biol., 10:41.
Voronina, V.A., Takemaru, K.-I.*, Treuting, P., Love, D., Grubb, B.R., Hajjar, A.M., Adams, A., Li, F.-Q. & Moon, R.T.* (2009)
Inactivaton of Chibby affects function of motile airway cilia.
J. Cell Biol., 185:225-233. *Co-correspondence.
Li, F.-Q., Mofunanya, A., Harris, K. & Takemaru, K.-I. (2008)
Chibby cooperates with 14-3-3 to regulate beta-catenin subcellular distribution and signaling activity.
J. Cell Biol., 181:1141-1154.
Research Highlight by Kritikou, E. (2008) AKTing in Wnt pathway. Nat. Rev. Mol. Cell Biol., 9:584.
Li, F.-Q., Singh, A.M., Mofunanya, A, Love, D., Terada, N., Moon, R.T. & Takemaru, K.-I. (2007)
Chibby promotes adipocyte differentiation through inhibition of beta-catenin signaling.
Mol. Cell. Biol., 27:4347-4354.
Takemaru, K.-I. (2006)
AfCS-Nature Molecule Pages, doi:10.1038/mp.a000506.01.
Rated as one of the top 10 most popular pages.
Takemaru, K.-I., Yamaguchi, S., Lee, Y.S., Zhang, Y., Carthew, R.W. & Moon, R.T. (2003)
Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway.
News and Views by Greaves, S. (2003) Small changes in Wnt signalling. Nat. Cell Biol., 5: 387.
Takemaru, K.-I. & Moon, R.T. (2000)
The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression.
J. Cell. Biol., 149:249-254.
Dept. of Pharmacology BST 7-182
Stony Brook, NY 11794-8651
Phone: (631) 444-7976
Fax: (631) 444-3218