Picture of Stephen Blacklow
Stephen Charles Blacklow, Ph.D., M.D.
Gustavus Adolphus Pfeiffer Professor of Biological Chemistry and Molecular Pharmacology

Our 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.  

 Research:

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. 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.

Address: 

LHRRB Building, Room 201B

45 Shattuck Street

Boston, MA 02115

Publications View
Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling.
Authors: Authors: Jarrett SM, Seegar TCM, Andrews M, Adelmant G, Marto JA, Aster JC, Blacklow SC.
Sci Signal
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Domain integration of ADAM family proteins: Emerging themes from structural studies.
Authors: Authors: Seegar TC, Blacklow SC.
Exp Biol Med (Maywood)
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A Flow-Extension Tethered Particle Motion Assay for Single-Molecule Proteolysis.
Authors: Authors: Drabek AA, Loparo JJ, Blacklow SC.
Biochemistry
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Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes.
Authors: Authors: Rogers JM, Waters CT, Seegar TCM, Jarrett SM, Hallworth AN, Blacklow SC, Bulyk ML.
Mol Cell
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Oncogenic Notch Promotes Long-Range Regulatory Interactions within Hyperconnected 3D Cliques.
Authors: Authors: Petrovic J, Zhou Y, Fasolino M, Goldman N, Schwartz GW, Mumbach MR, Nguyen SC, Rome KS, Sela Y, Zapataro Z, Blacklow SC, Kruhlak MJ, Shi J, Aster JC, Joyce EF, Little SC, Vahedi G, Pear WS, Faryabi RB.
Mol Cell
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Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition.
Authors: Authors: LaRochelle JR, Fodor M, Vemulapalli V, Mohseni M, Wang P, Stams T, LaMarche MJ, Chopra R, Acker MG, Blacklow SC.
Nat Commun
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The ectodomains determine ligand function in vivo and selectivity of DLL1 and DLL4 toward NOTCH1 and NOTCH2 in vitro.
Authors: Authors: Tveriakhina L, Schuster-Gossler K, Jarrett SM, Andrawes MB, Rohrbach M, Blacklow SC, Gossler A.
Elife
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Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains.
Authors: Authors: Wang J, Erazo T, Ferguson FM, Buckley DL, Gomez N, Muñoz-Guardiola P, Diéguez-Martínez N, Deng X, Hao M, Massefski W, Fedorov O, Offei-Addo NK, Park PM, Dai L, DiBona A, Becht K, Kim ND, McKeown MR, Roberts JM, Zhang J, Sim T, Alessi DR, Bradner JE, Lizcano JM, Blacklow SC, Qi J, Xu X, Gray NS.
ACS Chem Biol
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Dual Allosteric Inhibition of SHP2 Phosphatase.
Authors: Authors: Fodor M, Price E, Wang P, Lu H, Argintaru A, Chen Z, Glick M, Hao HX, Kato M, Koenig R, LaRochelle JR, Liu G, McNeill E, Majumdar D, Nishiguchi GA, Perez LB, Paris G, Quinn CM, Ramsey T, Sendzik M, Shultz MD, Williams SL, Stams T, Blacklow SC, Acker MG, LaMarche MJ.
ACS Chem Biol
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The Molecular Mechanism of Notch Activation.
Authors: Authors: Lovendahl KN, Blacklow SC, Gordon WR.
Adv Exp Med Biol
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