Notch proteins are the receptors in a highly conserved signal transduction system used to communicate information between cells that contact each other. The overarching goal of this Project is to elucidate the mechanism by which canonical ligands expressed on signal-sending cells activate Notch receptors on signal-receiving cells. Specifically, we propose two complementary sets of studies that will decipher two of the critical events that are required for ligand-induced Notch signaling:
Aim 1. To determine how Mind bomb induces ligand-dependent Notch signaling We will exploit the modular nature of mib and our expertise in structural and biochemical methods to determine the molecular logic underlying mind bomb function. Our top priorities will be i) to determine the structural basis for ligand-tail binding, and ii) to determine how the different Mib domains cooperate to transfer ubiquitin onto these tails.
Aim 2. To determine how ligand stimulation induces metalloprotease cleavage of Notch receptors One leading model for ligand-dependent activation of Notch posits that the endocytosis of bound ligand exerts a mechanical force on the receptor, releasing autoinhibitory interactions that protect the metalloprotease cleavage site. These studies will combine powerful single-molecule approaches and cellbased assays to evaluate the feasibility of the mechanical force model of Notch signal induction. Distinguishing between a mechanotransduction model and alternatives, such as allosteric "conformational switch" models, will substantially advance our understanding of the key events required for conveying Notch signals between adjacent cells, and will have important implications for efforts to target ligand-dependent Notch signaling. Moreover, the methods developed for probing the effect of mechanical force in Notch signal transduction will have general application in many other fields where the role of force in biology is under investigation. Together, pursuit of these aims will substantially advance our understanding of the key steps responsible for conveying Notch signals between adjacent cells. In addition, they will identify new potential targets for interventions designed to interfere with oncogenic Notch signaling in a wide spectrum of human cancers.
Ligand-dependent Notch signaling is important in many cancer-related processes, including tumor cell grovi/th/survival, angiogenesis, and the host immune response. Surprisingly little is known about the molecular details of how Notch ligands activate Notch receptors. This project will perform studies that fill this gap in current knowledge, and in doing so elucidate key aspects of Notch receptor activation that are likely to produce insights leading to new ways to target Notch in various human diseases, including cancer.
|Stein, Sarah J; Mack, Ethan A; Rome, Kelly S et al. (2016) Trib2 Suppresses Tumor Initiation in Notch-Driven T-ALL. PLoS One 11:e0155408|
|Bernasconi-Elias, P; Hu, T; Jenkins, D et al. (2016) Characterization of activating mutations of NOTCH3 in T-cell acute lymphoblastic leukemia and anti-leukemic activity of NOTCH3 inhibitory antibodies. Oncogene 35:6077-6086|
|Chiang, Mark Y; Wang, Qing; Gormley, Anna C et al. (2016) High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia. Blood 128:2229-2240|
|Guo, Bingqian; McMillan, Brian J; Blacklow, Stephen C (2016) Structure and function of the Mind bomb E3 ligase in the context of Notch signal transduction. Curr Opin Struct Biol 41:38-45|
|McMillan, Brian J; Tibbe, Christine; Jeon, Hyesung et al. (2016) Electrostatic Interactions between Elongated Monomers Drive Filamentation of Drosophila Shrub, a Metazoan ESCRT-III Protein. Cell Rep 16:1211-7|
|Xu, Xiang; Choi, Sung Hee; Hu, Tiancen et al. (2015) Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region. Structure 23:1227-35|
|McMillan, Brian J; Schnute, BjÃ¶rn; Ohlenhard, Nadja et al. (2015) A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases. Mol Cell 57:912-24|
|Wang, Hongfang; Zang, Chongzhi; Liu, X Shirley et al. (2015) The role of Notch receptors in transcriptional regulation. J Cell Physiol 230:982-8|
|Gordon, Wendy R; Zimmerman, Brandon; He, Li et al. (2015) Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell 33:729-36|
|Wang, Hongfang; Zang, Chongzhi; Taing, Len et al. (2014) NOTCH1-RBPJ complexes drive target gene expression through dynamic interactions with superenhancers. Proc Natl Acad Sci U S A 111:705-10|
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