BBS Faculty Member - Stephen Blacklow

Stephen Blacklow

Department of Biological Chemistry and Molecular Pharmacology

Harvard Medical School
LHRRB Building, Room 201B
240 Longwood Ave.
Boston, MA 02115
Tel: 617-432-5176
Fax: 617-525-4414
Lab Members: 8 postdoctoral fellows, 2 graduate students
Visit my lab page here.

The long-term goal of our research program is to understand the molecular logic of signal transduction, focusing on proteins implicated in human disease. The laboratory currently emphasizes structure-function studies in Notch signaling and maintains an ongoing interest in other oncogenic signaling pathways. 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. Our current efforts are directed toward understanding how activation is induced by ligands, how Notch cooperates with other factors to regulate target gene transcription, and how to inhibit Notch1 as a potential treatment for the aberrant signaling that occurs in more than half of human T-ALLs.

Last Update: 7/27/2015


For a complete listing of publications click here.



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. Developmental Cell. 2015;33(6):729-736.

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.

Wang NJ, Sanborn Z, Arnett KL, Bayston LJ, Liao W, Proby CM, Leigh IM, Collisson EA, Gordon PB, Jakkula L, Pennypacker S, Zou Y, Sharma M, North JP, Vemula SS, Mauro TM, Neuhaus IM, Leboit PE, Hur JS, Park K, Huh N, Kwok PY, Arron ST, Massion PP, Bale AE, Haussler D, Cleaver JE, Gray JW, Spellman PT, South AP, Aster JC*,
Blacklow SC*, Cho RJ*. Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma. Proc Natl Acad Sci U S A. 2011;108(43):17761-6.

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).

© 2015 by the President and Fellows of Harvard College