Biography

Postdoctoral Fellow, Harvard Medical School, Boston, MA, USA (Department of Cell Biology)

Mentor: Professor Junying Yuan

The role of oncogenes in regulating necroptosis and the significance of necroptosis potential in cancer was not known. During my postdoctoral work, in Junying Yuan’s laboratory at Harvard Medical School, I discovered the first links between necroptosis and cancer. Using high-throughput screening and cell biological methods, I found that escape from necroptosis is an oncogene-driven, pan-cancer, and prevalent phenomenon, suggesting that escape from necroptosis could be a hallmark of cancer. I identified oncogenic BRAF and AXL mutations as major drivers of this escape. Using molecular biology and biochemical methods, as well as mouse models of systemic inflammation, I found that necroptosis, surprisingly, requires the activity of the anti-inflammatory TAM kinases. Finally, I discovered that the initiator of necroptosis, RIPK1, mediates the sensing cytosolic glucose levels by the AMPK-mTORC1 pathway to regulate lysosomal homeostasis and cell response to energetic stress.

  • Identified a novel role of RIPK1 in glucose sensing by the AMPK-mTORC1 pathway.
  • Characterized the molecular mechanism of neonatal lethality of RIPK1-null mice.
  • Identified the TAM kinases as the first reported oncogenes that promote necroptosis.
  • Discovered BRAF and AXL as the first reported drivers of cancer escape from necroptosis.
  • Developed and published two omics data analysis software (senior author).
  • Contributed to three collaboration studies focused on deciphering novel drug-target interactions in the context of anti-tumor immunity and autophagy (senior author).
  • Contributed to 11 collaboration papers focused on the delineation of necroptosis regulation, its cross-talk with autophagy, and activation in ALS and MS.

PhD in Biochemistry and Molecular Biology, University of Dundee, Scotland, UK (MRC Protein Phosphorylation Unit)

Mentor: Professor Dario Alessi

The role of mTOR in activation of Akt was not defined and the inability of PDK1 inhibitors to block tumor growth was not understood. My PhD work in the laboratory of Dario Alessi at MRC Protein Phosphorylation Unit, produced two important mechanistic discoveries in the PI3K-PDK1-Akt-mTOR signaling. In collaboration with GlaxoSmithKline I characterized the first specific PDK1 inhibitor and found that unlike other kinases activated by PDK1, Akt retains activity upon inhibition of PDK1 due to its ability to co-localize with PDK1 at the plasma membrane. This finding explained why targeting PDK1 fails to inhibit tumor growth. I also discovered that Akt activation by PDK1 depends on Akt phosphorylation by mTOR. This discovery revised the model of Akt activation and provided a novel therapeutic strategy for increasing the efficacy of PDK1 inhibitors at blocking tumor growth: by co-targeting PDK1 and mTOR, Akt activity can be fully blocked, leading to a potent inhibition of cancer cell growth.

  • Discovered that Akt phosphorylation by mTOR is important for its activation by PDK1.
  • Characterized the first specific PDK1 inhibitor and identified a mechanism of cancer cell resistance to PDK1 inhibitors.
  • Performed SILAC phospho-proteomics screens - identified KIAA0802 as a novel target of the LKB1-MARK signaling pathway.
  • Independently developed mass spectrometry data analysis software, which resulted in a PI-level award.

MSc in Molecular Biology and Genetics, Summa Cum Laude, Bosphorus University, Istanbul, Turkey, and Harvard Medical School, Boston, MA, USA

Mentors: Professor Ahmet Koman, Asst. Professor Necla Birgul-Iyison, Professor Xi He

  • Identified novel transcriptional targets of the Wnt/β-catenin signaling pathway (MENA, BRI, and HSF2) and showed that MENA is a novel putative tumor-suppressor gene.

Internship, Baylor College of Medicine.

Mentor: Professor Henry F. Epstein

  • Discovered that C. elegans muscle myosin is a target of 26S proteasome.
  • Developed FRET-based quantitative methods for the analysis of myosin folding by chaperones Hsp90 and UNC-45.
  • Studied the role of filagenins in the C. elegans myofibril assembly.

BSc in Molecular Biology and Genetics, Magna Cum Laude, Bosphorus University, Istanbul, Turkey.

Mentors: Professor Esra Battaloglu, Dr. Ibrahim Baris

  • Identified novel GDAP1 mutations in Charcot-Marie-Tooth hereditary motor and sensory neuropathy patients.

Research Interest

  • Anti-tumor immunity
  • Cancer
  • Immunogenic cell death
  • Immunotherapy
  • Necroptosis signaling

Publications

Featured Publications LegendFeatured Publications

ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.
Wu Y, Zhang C, Liu X, He Z, Shan B, Zeng Q, Zhao Q, Zhu H, Liao H, Cen X, Xu X, Zhang M, Hou T, Wang Z, Yan H, Yang S, Sun Y, Chen Y, Wu R, Xie T, Chen W, Najafov A, Ying S, Xia H, Nat Commun 2021 04 12 1 2346
Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model.
Cen X, Chen Y, Xu X, Wu R, He F, Zhao Q, Sun Q, Yi C, Wu J, Najafov A, Xia H, Nat Commun 2020 11 11 1 5731
Modulating TRADD to restore cellular homeostasis and inhibit apoptosis.
Xu D, Zhao H, Jin M, Zhu H, Shan B, Geng J, Dziedzic SA, Amin P, Mifflin L, Naito MG, Najafov A, Xing J, Yan L, Liu J, Qin Y, Hu X, Wang H, Zhang M, Manuel VJ, Tan L, He Z, Sun ZJ, Lee VMY, Wagner G, Yuan J, Nature 2020 11 587 7832 133-138
Casein kinase-1?1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3.
Lee SY, Kim H, Li CM, Kang J, Najafov A, Jung M, Kang S, Wang S, Yuan J, Jung YK, Cell Death Dis 2019 12 10 12 923

Books

Featured Books Legend Featured Books

Honors & Awards

  • Science Signaling Editor’s Choice (Najafov et al., 2019, Mol Cell)
    (2019)
  • Innovator of the Year Award, University of Dundee, Scotland, UK
    (2012)
  • Selection of work by the Faculty of 1000 (Najafov et al., 2012, Biochem J)
    (2012)
  • Best Poster, EMBO Young Scientist Forum
    (2008)
  • Discovery PhD Scholarship, University of Dundee, Scotland, UK
    (2008)
  • Graduated with MSc High Honors (“Summa Cum Laude”)
    (2008)
  • Graduated with BSc Honors (“Magna Cum Laude”)
    (2006)
  • Bronze Medal, 11th International Biology Olympiad
    (2000)