@article{Johnson2023,
   author = {Johnson, Jared L. and Yaron, Tomer M. and Huntsman, Emily M. and Kerelsky, Alexander and Song, Junho and Regev, Amit and Lin, Ting-Yu and Liberatore, Katarina and Cizin, Daniel M. and Cohen, Benjamin M. and Vasan, Neil and Ma, Yilun and Krismer, Konstantin and Robles, Jaylissa Torres and van de Kooij, Bert and van Vlimmeren, Anne E. and Andrée-Busch, Nicole and Käufer, Norbert F. and Dorovkov, Maxim V. and Ryazanov, Alexey G. and Takagi, Yuichiro and Kastenhuber, Edward R. and Goncalves, Marcus D. and Hopkins, Benjamin D. and Elemento, Olivier and Taatjes, Dylan J. and Maucuer, Alexandre and Yamashita, Akio and Degterev, Alexei and Uduman, Mohamed and Lu, Jingyi and Landry, Sean D. and Zhang, Bin and Cossentino, Ian and Linding, Rune and Blenis, John and Hornbeck, Peter V. and Turk, Benjamin E. and Yaffe, Michael B. and Cantley, Lewis C.},
   title = {An atlas of substrate specificities for the human serine/threonine kinome},
   journal = {Nature},
   volume = {613},
   number = {7945},
   pages = {759-766},
   abstract = {Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.},
   ISSN = {1476-4687},
   DOI = {10.1038/s41586-022-05575-3},
   url = {https://doi.org/10.1038/s41586-022-05575-3},
   year = {2023},
   type = {Journal Article}
}

@article{Yaffe2001,
   author = {Yaffe, Michael B. and Leparc, German G. and Lai, Jack and Obata, Toshiyuki and Volinia, Stefano and Cantley, Lewis C.},
   title = {A motif-based profile scanning approach for genome-wide prediction of signaling pathways},
   journal = {Nature Biotechnology},
   volume = {19},
   number = {4},
   pages = {348-353},
   abstract = {The rapid increase in genomic information requires new techniques to infer protein function and predict protein–protein interactions. Bioinformatics identifies modular signaling domains within protein sequences with a high degree of accuracy. In contrast, little success has been achieved in predicting short linear sequence motifs within proteins targeted by these domains to form complex signaling networks. Here we describe a peptide library-based searching algorithm, accessible over the World Wide Web, that identifies sequence motifs likely to bind to specific protein domains such as 14-3-3, SH2, and SH3 domains, or likely to be phosphorylated by specific protein kinases such as Src and AKT. Predictions from database searches for proteins containing motifs matching two different domains in a common signaling pathway provides a much higher success rate. This technology facilitates prediction of cell signaling networks within proteomes, and could aid in the identification of drug targets for the treatment of human diseases.},
   ISSN = {1546-1696},
   DOI = {10.1038/86737},
   url = {https://doi.org/10.1038/86737},
   year = {2001},
   type = {Journal Article}
}

@article{Yaron-Barir2024,
   author = {Yaron-Barir, Tomer M. and Joughin, Brian A. and Huntsman, Emily M. and Kerelsky, Alexander and Cizin, Daniel M. and Cohen, Benjamin M. and Regev, Amit and Song, Junho and Vasan, Neil and Lin, Ting-Yu and Orozco, Jose M. and Schoenherr, Christina and Sagum, Cari and Bedford, Mark T. and Wynn, R. Max and Tso, Shih-Chia and Chuang, David T. and Li, Lei and Li, Shawn S. C. and Creixell, Pau and Krismer, Konstantin and Takegami, Mina and Lee, Harin and Zhang, Bin and Lu, Jingyi and Cossentino, Ian and Landry, Sean D. and Uduman, Mohamed and Blenis, John and Elemento, Olivier and Frame, Margaret C. and Hornbeck, Peter V. and Cantley, Lewis C. and Turk, Benjamin E. and Yaffe, Michael B. and Johnson, Jared L.},
   title = {The intrinsic substrate specificity of the human tyrosine kinome},
   journal = {Nature},
   volume = {629},
   number = {8014},
   pages = {1174-1181},
   abstract = {Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth1. Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome1–3. How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood4–7. Here we used combinatorial peptide arrays to profile the substrate sequence specificity of all human Tyr kinases. Globally, the Tyr kinases demonstrate considerable diversity in optimal patterns of residues surrounding the site of phosphorylation, revealing the functional organization of the human Tyr kinome by substrate motif preference. Using this information, Tyr kinases that are most compatible with phosphorylating any Tyr site can be identified. Analysis of mass spectrometry phosphoproteomic datasets using this compendium of kinase specificities accurately identifies specific Tyr kinases that are dysregulated in cells after stimulation with growth factors, treatment with anti-cancer drugs or expression of oncogenic variants. Furthermore, the topology of known Tyr signalling networks naturally emerged from a comparison of the sequence specificities of the Tyr kinases and the SH2 phosphotyrosine (pTyr)-binding domains. Finally we show that the intrinsic substrate specificity of Tyr kinases has remained fundamentally unchanged from worms to humans, suggesting that the fidelity between Tyr kinases and their protein substrate sequences has been maintained across hundreds of millions of years of evolution.},
   ISSN = {1476-4687},
   DOI = {10.1038/s41586-024-07407-y},
   url = {https://doi.org/10.1038/s41586-024-07407-y},
   year = {2024},
   type = {Journal Article}
}