Picture of Stephen Blacklow

Stephen Charles Blacklow, Ph.D., M.D.

Gustavus Adolphus Pfeiffer Professor of Biological Chemistry and Molecular Pharmacology

For many years, my laboratory has focused on understanding fundamental mechanisms of signal transduction at the structural and molecular level. Our work has emphasized the investigation of how information is communicated across the plasma membrane. Current studies in the laboratory center on the Notch pathway, which relies on cell-cell contact to transmit a signal. Notch signals influence a wide spectrum of cell fate decisions, both during development and in adult organisms, yet dysregulated Notch signaling has been implicated in the pathogenesis of a number of human cancers. The Notch proteins are single-pass transmembrane receptors that convey signals upon activation by transmembrane ligands expressed on neighboring cells. 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. Our current efforts are directed toward answering a number of unresolved questions about how proteins genetically implicated in the Notch pathway modulate signaling in normal and cancer contexts. Priorities include understanding the detailed sequence of events that occur at the plasma membrane upon signal activation, uncovering the molecular mechanism of normal and pathogenic activation of Notch receptors by ADAM-family metalloproteases, elucidating how Notch cooperates with other nuclear factors to control target gene transcription, and understanding how negative feedback regulators fine-tune signaling.  

Dr. Blacklow is currently the Gustavus Adolphus Pfeiffer Professor and Chair of the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School, and a member of the Department of Cancer Biology at the Dana Farber Cancer Institute.

Research led by Dr. Blacklow’s team has shown how cell surface receptors can convey a developmental signal directly from one contacting cell surface to the next and then from the membrane to the nucleus. He has elucidated key molecular events in Notch signal transduction, a conserved cell-cell communication system that influences cell fate decisions in all metazoan organisms, and that is frequently hijacked as an oncogenic driver in human leukemia. His research on the Notch pathway has led to the development of new investigational therapies for hematologic malignancies such as T cell acute lymphocytic leukemia (ALL).

Dr. Blacklow was a recipient of the National Cancer Institute’s prestigious Outstanding Investigator Award in 2017, and elected to the Association of American Physicians in 2018. Dr. Blacklow directed the MD-PhD Program in Basic and Translational Sciences at Harvard Medical School and has served on Advisory Committees for pre-clinical departments, graduate programs, and MD-PhD programs at several major research universities and institutions, including Stanford, the University of Pennsylvania, and the Memorial Sloan Kettering Cancer Center.

Dr. Blacklow received his MD and PhD degrees from Harvard University in 1991, completed his residency in Clinical Pathology at Brigham and Women’s Hospital, and carried out postdoctoral research at the Whitehead Institute with Dr. Peter S. Kim.

Publications View
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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Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
Authors: Authors: LaRochelle JR, Fodor M, Ellegast JM, Liu X, Vemulapalli V, Mohseni M, Stams T, Buhrlage SJ, Stegmaier K, LaMarche MJ, Acker MG, Blacklow SC.
Bioorg Med Chem
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Structural Basis for Regulated Proteolysis by the a-Secretase ADAM10.
Authors: Authors: Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC.
Cell
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MAFB enhances oncogenic Notch signaling in T cell acute lymphoblastic leukemia.
Authors: Authors: Pajcini KV, Xu L, Shao L, Petrovic J, Palasiewicz K, Ohtani Y, Bailis W, Lee C, Wertheim GB, Mani R, Muthusamy N, Li Y, Meijerink JPP, Blacklow SC, Faryabi RB, Cherry S, Pear WS.
Sci Signal
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Diffuse Staining for Activated NOTCH1 Correlates With NOTCH1 Mutation Status and Is Associated With Worse Outcome in Adenoid Cystic Carcinoma.
Authors: Authors: Sajed DP, Faquin WC, Carey C, Severson EA, H Afrogheh A, A Johnson C, Blacklow SC, Chau NG, Lin DT, Krane JF, Jo VY, Garcia JJ, Sholl LM, Aster JC.
Am J Surg Pathol
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A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas.
Authors: Authors: Ryan RJH, Petrovic J, Rausch DM, Zhou Y, Lareau CA, Kluk MJ, Christie AL, Lee WY, Tarjan DR, Guo B, Donohue LKH, Gillespie SM, Nardi V, Hochberg EP, Blacklow SC, Weinstock DM, Faryabi RB, Bernstein BE, Aster JC, Pear WS.
Cell Rep
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Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations.
Authors: Authors: McMillan BJ, Zimmerman B, Egan ED, Lofgren M, Xu X, Hesser A, Blacklow SC.
Glycobiology
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Structural Basis for Regulation of ESCRT-III Complexes by Lgd.
Authors: Authors: McMillan BJ, Tibbe C, Drabek AA, Seegar TCM, Blacklow SC, Klein T.
Cell Rep
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