Ayaz Najafov, Ph.D.
Assistant Professor

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. Using high-throughput screening, bioinformatics, and methods in cell and molecular biology, 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.

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. 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.

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 I identified and contributed to the identification of novel transcriptional targets of the Wnt/β-catenin signaling pathway (MENA, BRI, and HSF2) and demonstration that MENA is a novel putative tumor-suppressor gene.

BSc in Molecular Biology and Genetics, Magna Cum Laude, Bosphorus University, Istanbul, Turkey. Mentors: Professor Esra Battaloglu, Dr. Ibrahim Baris I identified novel GDAP1 mutations in Charcot-Marie-Tooth hereditary motor and sensory neuropathy patients.

 

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

Featured Publications

RIPK1 Promotes Energy Sensing by the mTORC1 Pathway.

Najafov A, Luu HS, Mookhtiar AK, Mifflin L, Xia HG, Amin PP, Ordureau A, Wang H, Yuan J, Mol Cell 2021 01 81 2 370-385.e7

TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL.

Najafov A, Mookhtiar AK, Luu HS, Ordureau A, Pan H, Amin PP, Li Y, Lu Q, Yuan J, Mol Cell 2019 08 75 3 457-468.e4

GECO: gene expression correlation analysis after genetic algorithm-driven deconvolution.

Najafov J, Najafov A, Bioinformatics 2019 01 35 1 156-159

BRAF and AXL oncogenes drive RIPK3 expression loss in cancer.

Najafov A, Zervantonakis IK, Mookhtiar AK, Greninger P, March RJ, Egan RK, Luu HS, Stover DG, Matulonis UA, Benes CH, Yuan J, PLoS Biol 2018 08 16 8 e2005756

CrossCheck: an open-source web tool for high-throughput screen data analysis.

Najafov J, Najafov A, Sci Rep 2017 07 7 1 5855

Necroptosis and Cancer.

Najafov A, Chen H, Yuan J, Trends Cancer 2017 04 3 4 294-301

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

 Featured Books

PCR Guru: An Ultimate Benchtop Reference for Molecular Biologists

Najafov A, Hoxhaj G (2016). Elsevier, Academic Press

Western Blotting Guru

Najafov A, Hoxhaj G (2017). Elsevier, Academic Press

• 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)