Homeostatic Regulation of Adult Stem Cells
Homeostatic turnover in adult tissues is governed by the interplay of a multitude of signalling pathways that are often triggered by niche cells providing diverse ligands to support stem cells. Upon tissue damage, adult stem cells rapidly proliferate to restore the loss and reinstate homeostasis; regulatory signalling that governs proliferation and differentiation of stem cells enable this damage response. De-regulation of these processes on the other hand results in either hyperplasia or loss of stem cells. In the intestine, fine-tuning of this regulation is carried out not only by crosstalk between different pathways, but also by modulation of activity within individual pathways at several levels. An important class of modulators are E3 ubiquitin ligases. In cells, E3 ligases commonly promote degradation of their target proteins by proteasomes. At the plasma membrane, however, E3 ligases regulate levels of transmembrane proteins by promoting ubiquitin-dependent endocytosis. Mib1, an E3 for Notch ligands, has a crucial role in Notch ligand activation in niche cells that, in turn, promotes Notch signalling in stem cells (Development 2005, Neuron 2008, and Gastroenterology 2009). RNF43 and ZNRF3 attenuate Wnt activation in intestinal stem cells by functioning as E3s for Wnt receptors (Nature 2012). Thus to date, we have learned about E3 ligases working in the Notch and Wnt pathways in adult stem cells. In light of this, it seems probable that other E3 ligases, with important roles in adult stem cell biology, remain to be identified. Our research focus is on identifying and understanding the role of novel E3 ubiquitin ligases in homeostatic regulation of stem cells.
Information above is copied from : http://www.stemcells.cam.ac.uk/researchers/principal-investigators/bon-kyoung-koo
- Koo B K, Stange D E et al. Controlled gene expression in primary Lgr5 organoid cultures. Nature Methods 2011 Dec 4; 9(1) : 81-3
- Kim H A, Koo B K et al. Notch counteracts Wnt-beta-catenin signaling through chromatin modification in mouse and human colorectal cancer. J Clin Invest 2012 Sep 4; 122(9) : 3248-59
- Koo BK et al. Tumour suppressor RNF43 is a stem cell E3 ligase that induces endocytosis of Wnt receptors. Nature 2012 Aug 30; 488(7413) : 665-9
- Stange D E, Koo B K et al. Differentiated Troy+ chief cells act as 'reserve' stem cells to generate all lineages of the stomach epithelium. Cell 2013 [in press]