Cell Adhesion & Polarity
The main cause of mortality in cancer patients is secondary tumours, which are mediated by metastatic epithelial cancer cells. As a matter of fact, epithelial cancers constitute ~85% of all cancers including primary tumours. For these reasons, a detailed understanding of epithelial cells is crucial to combat cancer. Like many other cell types, epithelial cells have the ability to adhere to one another and form a specific multicellular structure (epithelium), which is fundamental to normal cell development and morphogenesis of human tissues. Cancer disrupts normal cell adhesion and polarity functions, permitting the spread of cancer cells from the primary cancer site to other locations in the body (metastasis). Cell adhesion and polarity are both coupled with intracellular signalling and cytoskeletal assembly. Together these cellular processes control the shape and motility of cells in a dynamic manner. The cell-cell adhesion molecule cadherin and its associated factors called catenins play critical roles in maintaining the stable cell-cell interaction. Loss of E-cadherin function has been implicated with tumourgenesis and metastatic potential of cancers. Not surprisingly, recent studies have revealed that the cadherin adhesion system is coupled with cell polarity proteins that co-localize at the apical side of the epithelium. Using X-ray crystallography and NMR spectroscopy, we plan to determine the structural basis of the cadherin-mediated cell-cell interaction, and are working to determine the mechanisms by which the cadherin function is regulated through interaction with intracellular proteins and cytoskeletal components. Both E-cadherin and p120-catenin are well-known targets for Src protein kinases. We are investigating how Src-dependent protein phosphorylation alters the structure and function of the cadherin-catenin complex. We are also studying the Par complex, which consists of a number of cell polarity proteins. Structural characterization of these protein-protein interactions would be crucial in understanding how cell polarity and cell adhesion phenomena are dynamically regulated. We hope to reveal novel insights to support the development of therapeutics to reduce or abolish the metastatic potential of cancer cells.
Sandí MJ, Marshall CB, Balan M, Coyaud É, Zhou M, Monson DM, Ishiyama N, Chandrakumar AA, La Rose J, Couzens AL, Gingras AC, Raught B, Xu W, Ikura M, Morrison DK, Rottapel R. MARK3-mediated phosphorylation of ARHGEF2 couples microtubules to the actin cytoskeleton to establish cell polarity. Science Signal . 2017 Oct 31;10(503). pii: eaan3286.
Wood MN, Ishiyama N, Singaram I, Chung CM, Flozak AS, Yemelyanov A, Ikura M, Cho W, Gottardi CJ. a-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion.J Cell Biol 2017 Nov 6;216(11):3767-3783.
Zheng W, Umitsu M, Jagan I, Tran CW, Ishiyama N, BeGora M, Araki K, Ohashi PS, Ikura M, Muthuswamy SK. An interaction between Scribble and the NADPH oxidase complex contrals M1 macrophage polarization and function. Nat Cell Biol 2016 Nov;18(11):1244-1252.
Escobar DJ, Desai R, Ishiyama N, Folmsbee SS, Novak MN, Flozak AS, Daugherty RL, Mo R, Nanavati D, Sarpal R, Leckband D, Ikura M, Tepass U, Gottardi CJ. a-Catenin phosphorylation promotes intercellular adhesion through a dual-kinase mechanism. J Cell Biol 2015 Mar 15;128(6):1150-65.
Desai R, Sarpal R, Ishiyama N, Pellikka M, Ikura M, Tepass U. Monomeric a-catenin links cadherin to the actin cytoskeleton. Nat Cell Biol 2013 Mar;15(3):261-73.
Nanes BA, Chiasson-MacKenzie C, Lowery AM, Ishiyama N, Faundez V, Ikura M, Vincent PA, Kowalczyk AP. p120-catenin binding masks an endocytic signal conserved in classical cadherins. J Cell Biol 2012 Oct 15;199(2):365-80.
Yang Z, Xue B, Umitsu M, Ikura M, Muthuswamy SK, Neel BG. The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold. (2012) Mol Cell 47(3):469-83.
Meiri D, Marshall CB, Greeve MA, Kim B, Balan M, Suarez F, Bakal C, Wu C, Larose J, Fine N, Ikura M, Rottapel R. Mechanistic insight into the microtubule and actin cytoskeleton coupling through dynein-dependent RhoGEF inhibition. (2012) Mol Cell 45(5):642-55.
Ishiyama N, Lee SH, Liu S, Li GY, Smith MJ, Reichardt LF, Ikura M. Dynamic and static interactions between p120 catenin and E-cadherin regulate the stability of cell-cell adhesion.(2010) Cell 141(1):117-28.
Hayashi I, Plevin MJ, Ikura M. CLIP170 autoinhibition mimics intermolecular interactions with p150Glued or EB1 (2007) Nat Struct Mol Biol .14(10):980-1.
Plevin, M.J., Zhang J., Guo C., Roeder R.G., Ikura M. The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain (2006) Proc Natl Acad Sci USA. 103(27):10242-7.
Hayashi, I., Wilde A., Mal T. K., Ikura M. Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex (2005) Mol. Cell (19)4: 449-460.