Yonghao Yu, PhD

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Overview

Dr. Yu received his B.S. in Chemistry from Fudan University (Shanghai, China) in 2001, and then his Ph.D. in Chemistry from the University of California, Berkeley in 2006. His doctoral research with Dr. Julie Leary focused on mass spectrometry-based proteomic technologies and chemical biology of novel protein modifications. Dr. Yu completed his postdoctoral training (2007-2011) with Drs. Steven Gygi and John Blenis in the Department of Cell Biology at Harvard Medical School. During his postdoctoral training, Dr. Yu studied the function and regulation of phosphorylation-dependent signaling mechanisms in cell growth control. Dr. Yu began his independent research career in 2012 in the Department of Biochemistry at the University of Texas Southwestern Medical Center, where he was a CPRIT scholar in cancer research and a Virginia Murchison Linthicum Scholar in Medical Research. He was promoted to Associate Professor with tenure in 2017. In 2022, Dr. Yu was recruited to join the Department of Molecular Pharmacology and Therapeutics at Columbia University Irving Medical Center as a full professor. Using a multidisciplinary approach, his lab has contributed significantly to our molecular understanding of novel covalent protein modifications in the human proteome. Dr. Yu is also particularly interested in translating the mechanistic insights into novel therapeutic strategies for the relevant diseases, including cancer, diabetes, and neurodegeneration. Through the years, Dr. Yu has been involved in many teaching and scientific outreach activities. He has also served on many NIH and DoD advisory panels, including as a current member of the NIH Enabling Bioanalytical and Imaging Technologies (EBIT) Study Section.

Academic Appointments

  • Professor in the Department of Molecular Pharmacology and Therapeutics

Gender

  • Male

Research

Our understanding of how the biology of various diseases relates to the central dogma that DNA encodes RNA, which encodes protein has been buoyed by rapid technological advances in DNA and RNA sequencing and has led to some of the first advances in personalized medicine. However, characterization of the final and arguably most actionable element of the central dogma, protein, has lagged behind. Among the various proteomic parameters, a comprehensive description of the landscape of covalent protein modifications in any given cell is particularly challenging. Our research efforts are highly multidisciplinary, which have been largely focused on two programs, i.e., (1) novel protein posttranslational modifications (PTMs), and (2) novel covalent protein modifications by small molecule drugs. Regarding (1), the entire repertoire of protein posttranslational modifications (PTMs) is enormous, with ~400 different known types, and many more unknown ones (i.e., the “dark proteome”). PTMs are inaccessible by genomic sequencing tools. Instead, they are almost exclusively analyzed by proteomic technologies. The functional characterization of a PTM event ultimately depends on the unequivocal assignment of the modification site. However, the chemical natures of PTMs are diverse, and many types of PTMs are not amenable to traditional proteomic technologies for site-localization with single amino acid resolution because they are, for example, labile, heterogeneous or low-abundance. We have developed a multidisciplinary program (i.e., chemical biology, quantitative-/chemo-proteomics, computation biology, biochemistry, molecular biology and animal models) towards the functional analyses of a number of important PTMs, including protein tyrosine sulfation, phosphorylation and Poly-ADP-ribosylation. Regarding (2), besides these naturally occurring PTMs, covalent protein modification has been increasingly appreciated as a novel therapeutic modality. The current efforts on drug development have been mostly focused on targeting a small fraction of the human proteome with good pharmacological tractability (e.g., kinases). It has been estimated, however, that approximately 90% of human proteins (e.g., transcription factors, adaptors and intrinsically disordered proteins) have not been effectively targeted by small-molecule drugs, because, for example, they lack traditionally defined binding pockets. We have also been particularly active in the development of covalent protein modification and chemoproteomic technologies that potentially will revolutionize the principle of drug development by pushing the boundaries of the druggable proteome. 

Selected Publications

  1. Kim C, Wang XD, Liu Z, Zha S, Yu Y. Targeting Scaffolding Functions of Enzymes Using PROTAC Approaches. Biochemistry. 2022 Jul 14
  2. Zi Z, Zhang Z, Feng Q, Kim C, Wang XD, Scherer PE, Gao J, Levine B, Yu Y. Quantitative phosphoproteomic analyses identify STK11IP as a lysosome-specific substrate of mTORC1 that regulates lysosomal acidification. Nature Communications. 2022 Apr 1;13(1):1760.
  3. Kim C, Chen C, Yu Y. Avoid the trap: targeting PARP1 beyond human malignancy. Cell Chemical Biology., 2021 Apr 15;28(4):456-462.
  4. Kim C, Wang X, Yu Y. PARP1 Inhibitors Trigger Innate Immunity via PARP1 Trapping-induced DNA Damage Response, eLife, 2020 Aug 26;9. doi: 10.7554/eLife.60637
  5. Wang S, Han L, Han J, Li P, Ding Q, Zhang QJ, Liu ZP, Chen C, Yu Y. Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nature Chemical Biology. 2019 Dec;15(12):1223-1231.
  6. Wang XD, Hu R, Ding Q, Savage TK, Huffman KE, Williams N, Cobb MH, Minna JD, Johnson JE, Yu Y. Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells. Nature Communications. 2019 Jul 19;10(1):3201.
  7. Wang Z, Ma J, Miyoshi C, Li Y, Sato M, Ogawa Y, Lou T, Ma C, Gao X, Lee C, Fujiyama T, Yang X, Zhou S, Hotta-Hirashima N, Klewe-Nebenius D, Ikkyu A, Kakizaki M, Kanno S, Cao , Takahashi S, Peng J, Yu Y, Funato H, Yanagisawa M, Liu Q, “Quantitative phosphoproteomic analysis of the molecular substrates of sleep need”, Nature, (2018)
  8. Zhen Y, Zhang Y, Yu Y., “A cell line-specific atlas of PARP-mediated protein Asp/Glu-ADP-ribosylation in breast cancer”, Cell Reports, 8, 2326, (2017).
  9. Zhang Y, Zhang Y and Yu Y., “Global Phosphoproteomic analysis of Insulin/Akt/mTORC1/S6K signaling in Rat Hepatocytes”, Journal of Proteome Research, 16, 2825, (2017).
  10. Gibson BA, Zhang Y, Jiang H, Hussey KM, Shrimp JH, Lin H, Schwede F, Yu Y, Kraus WL. “Chemical genetic discovery of PARP targets reveals a role for PARP-1 in transcription elongation”, Science, (research article), 353, 45-50, (2016).
  11. Ding M, Bruick R, and Yu Y*. “Secreted IGFBP5 mediates mTORC1-dependent feedback inhibition of IGF-1 signaling”, Nature Cell Biology, 18, 319, (2016).
  12. Xiang, S., Kato, M., Wu, L., Lin, Y., Ding, M., Zhang, Y., Yu, Y. and McKnight, S. L. “The LC Domain of hnRNPA2 adopts similar conformations in hydrogel polymers, liquid-like droplets and nuclei”, Cell, 163, 829-839 (2015).
  13. Wang J, Zhang Y and Yu Y. “Crescendo: A Protein Sequence Database Search Engine for Tandem Mass Spectra”, J. Am. Soc. Mass. Spectrom., 26, 1077 (2015).
  14. Zhang, Y., Wang, J., Ding, M. and Yu, Y. “Site-Specific Characterization of the Asp- and Glu-ADP-ribosylated Proteome”. Nature Methods, 10(10):981-4 (2013).
  15. Yu, Y., Yoon, S., Poulogiannis, G., Yang, Q., Ma, M., Villen, J., Kubica, N., Hoffman, G., Cantley, L. C., Gygi, S. P. & Blenis, J. “Phosphoproteomic Analysis Identifies Grb10 as an mTORC1 Substrate That Negatively Regulates Insulin Signaling” Science, 332(6035), 1322-1326 (2011).