Stephen C. Blacklow, M.D., Ph.D.
Chair, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School
Member, Department of Cancer Biology, Dana Farber Cancer Institute
The Blacklow laboratory studies biochemical and molecular mechanisms of signal transduction. A major focus is on elucidating key events mediated by the Notch signaling pathway in health and disease.
The primary long-term goal of our research program is to elucidate molecular and biophysical mechanisms of signal transduction. The laboratory currently emphasizes structure-function studies in Notch signaling and maintains an ongoing interest in other signal transduction systems implicated in the pathogenesis of cancer and other diseases.
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. 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.
Although Notch receptors are large and complex, all family members contain an extracellular ligand-binding domain, a conserved extracellular juxtamembrane region that maintains the receptor in a resting conformation prior to ligand-induced activation, and an intracellular ankyrin repeat domain required to activate transcription. Mutations in the juxtamembrane region cause increased signaling and occur frequently in human T-cell acute leukemias (T-ALL), identifying Notch as a therapeutic target in these tumors. One area of current focus centers on understanding how activation is induced by ligands. Another key question we are addressing is how Notch cooperates with other factors to regulate target gene transcription. A third area of exploration is to elucidate how Notch modifiers and downstream effectors modulate and tune the Notch response in normal and pathogenic states.
Uljon S, Xu X, Durzynska I, Stein S, Adelmant G, Marto JA, Pear WS, Blacklow SC. Structural Basis for Substrate Selectivity of the E3 Ligase COP1. Structure. 2016;24(5):687-96. PMCID: PMC4856590
McMillan BJ, Ohlenhard N, Schnute B, Zimmerman B, Miles L, Beglova N, Klein T, and Blacklow SC. A Tail of Two Sites: A Bipartite Mechanism for Recognition of Notch Ligands by Mind Bomb E3 Ligases. Molecular Cell 2015;57(5):912-24. PMCID: PMC4355479.
Guo, B, McMillan, BJ, and Blacklow, SC. Structure and Function of the Mind bomb E3 ligase in the context of Notch Signal Transduction. Current Opinion in Structural Biology 2016;41:38-45. PMCID: in process.
Gordon WR, Zimmerman B, He L, Miles LJ, Huang J, Tiyanont K, McArthur DG, Aster JC, Perrimon N, Loparo JJ, Blacklow SC. Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. Dev Cell 2015;33(6):729-736. PMCID: PMC4481192.
Arnett, KA, Hass, M, McArthur, DG, Ilagan, MXG, Aster, JC, Kopan, R, and Blacklow SC. Structural and Mechanistic Insights into Cooperative Assembly of Dimeric Notch Transcription Complexes. Nature Structural and Molecular Biology 2010;17(11):1312-7 (Cover article). PMCID: PMC3024583
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