Stephen C. Blacklow
Department of PathologyBrigham and Women's Hospital
New Research Building, Room 652D
77 Avenue Louis Pasteur
Boston, MA 02115
The long-term goal of our research program is to understand the molecular logic of cell-surface receptors, focusing on proteins implicated in human disease. The laboratory currently emphasizes structure-function studies in Notch signaling and maintains an ongoing interest in proteins of the LDL receptor family.
Notch proteins are single-pass transmembrane receptors that convey signals upon activation by transmembrane ligands expressed on neighboring cells. The signals transduced by Notch receptors play a central role in cell fate decisions both during embryonic development and in adult tissue homeostasis. The essential role of Notch signaling during development is evident from the embryonic lethality that is associated with deficiencies in Notch signaling in various model organisms, including worms, flies and mice.
In normal Notch signaling, ligand binding initiates signaling by triggering a process called regulated intramembrane proteolysis, releasing the intracellular part of Notch (ICN) from the membrane. In canonical Notch signaling, ICN ultimately enters the nucleus, where it assembles into a transcriptional activation complex to induce the expression of Notch target genes. Significantly, the discovery that mutations in NOTCH1, one of four mammalian Notch receptors, are frequently found in human T cell acute lymphocytic leukemia moved NOTCH1 to the forefront in understanding disease pathogenesis and also pointed to NOTCH1 as a mechanism-based therapeutic target.
Our current efforts in the Notch signaling area are directed toward both basic and applied questions. At the basic mechanism level, we are interested in elucidating how activation is induced by ligands and how Notch cooperates with other factors to regulate target gene transcription. In more applied studies, we are part of a collaborative research team working toward targeting the Notch signaling pathway in pursuit of mechanism-based therapy for T-cell acute leukemia and other cancers.
Aster, J.C., Pear, W.S., and Blacklow, S.C. (2008). Notch Signaling in Leukemia. Annual Rev. Pathol. 3: 587-613.
Del Bianco, C., Aster, J.C., and Blacklow, S,C. (2008). Mutational and energetic studies of Notch1 transcription complexes. Journal of Molecular Biology 376(1): 131-40.
Gordon, W.R., Vardar-Ulu, D., Histen, G., Sanchez-Irizarry, C., Aster, J.C., and Blacklow, S.C. (2007). Structural basis for autoinhibition of Notch. Nature Structural Molecular Biology 14(4): 295-300.
Nam, Y., Sliz, P., Pear, W.S., Aster, J.C., Blacklow, S.C. (2007). Cooperative assembly of higher-order Notch complexes functions as a switch to induce transcription. Proc. Natl. Acad. Sci. USA 104(7): 2103-8.
Nam, Y., Sliz, P., Song, L., Aster, J.C., Blacklow, S.C. (2006). Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124(5): 973-83.
Fisher, C., Beglova, N., Blacklow, S.C. (2006). Structure of an LDLR-RAP Complex Reveals a General Mode for Ligand Recognition by Lipoprotein Receptors. Molecular Cell 22(2): 277-83.
Jeon, H. and Blacklow, S.C. (2005). Structure and physiologic function of the low-density lipoprotein receptor. Annual Rev. Biochem. 74: 535-62.
Beglova, N., Jeon, H., Fisher, C., and Blacklow, S.C. (2004). Cooperation by fixed and low pH-inducible interfaces controls lipoprotein release by the LDL receptor. Molecular Cell 16(2): 281-92.
Page created and maintained by Xaq Pitkow