The intrinsic substrate specificity of the human tyrosine kinome

• 成果类型: Article
• 署名作者: Yaron-Barir, Tomer M.; Joughin, Brian A.; Huntsman, Emily M.; Kerelsky, Alexander; Cizin, Daniel M.; Cohen, Benjamin M.; Regev, Amit; Song, Junho; Vasan, Neil; Lin, Ting-Yu; Orozco, Jose M.; Schoenherr, Christina; Sagum, Cari; Bedford, Mark T.; Wynn, R. Max; Tso, Shih-Chia; Chuang, David T.; Li, Lei; Li, Shawn S-C; Creixell, Pau; Krismer, Konstantin; Takegami, Mina; Lee, Harin; Zhang, Bin; Lu, Jingyi; Cossentino, Ian; Landry, Sean D.; Uduman, Mohamed; Blenis, John; Elemento, Olivier; Frame, Margaret C.; Hornbeck, Peter V.; Cantley, Lewis C.; Turk, Benjamin E.; Yaffe, Michael B.; Johnson, Jared L.
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Columbia University; Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Columbia University; NewYork-Presbyterian Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; University of Edinburgh; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Health & Rehabilitation Sciences; Western University (University of Western Ontario); University of Cambridge; Cancer Research UK; CRUK Cambridge Institute; Massachusetts Institute of Technology (MIT); Cell Signaling Technology; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Yale University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6282
• DOI: 10.1038/s41586-024-07407-y
• 发表日期: 2024-05-30
• 页码: 1174-+
• 关键词: crystal-structure; protein-kinases; signaling networks; plasma-membrane; receptor; activation; domain; RECOGNITION; reveals; complex

摘要

Phosphorylation of proteins on tyrosine (Tyr) residues evolved in metazoan organisms as a mechanism of coordinating tissue growth(1). Multicellular eukaryotes typically have more than 50 distinct protein Tyr kinases that catalyse the phosphorylation of thousands of Tyr residues throughout the proteome(1-3). How a given Tyr kinase can phosphorylate a specific subset of proteins at unique Tyr sites is only partially understood(4-7). 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.