Abstract 3487: An atlas of substrate specificities for the human tyrosine kinome

Abstract

Abstract Numerous physiological processes are governed by tyrosine phosphorylation. The protein tyrosine kinases that carry this out are dysregulated in a variety of cancers and are the targets of efficacious drugs. For most tyrosine kinases, we have a very limited understanding of their downstream signaling pathways and phosphorylation targets. Conversely, thousands of tyrosine phosphorylation events have so far been experimentally identified, and the overwhelming majority of these do not have an associated kinase. In this work, we have utilized peptide arrays to determine the substrate sequence specificity for the human tyrosine kinome, comprising 46 receptor tyrosine kinases, 32 nonreceptor tyrosine kinases, and 14 noncanonical tyrosine kinases. Nearly every kinase we profiled favored tyrosines that were positioned next to phosphorylated amino acids, indicating that PTM priming and crosstalk are general properties of the tyrosine kinome. Comparisons with C. elegans orthologs suggested that tyrosine kinase substrate motifs have remained conserved throughout metazoan evolution. When we computationally utilized our dataset to identify kinases for tyrosine substrates, our predictions were in strong accordance with published reports. When applied to high-throughput tyrosine phosphoproteomics datasets, we could decipher the kinases involved in cellular responses to growth factors, oncogenic mutations, and targeted inhibitors. Together, this work uncovers fundamental rules of substrate selection for nearly the entire human tyrosine kinome and provides a comprehensive resource for connecting tyrosine phosphorylation events with their kinases and signaling pathways. Citation Format: Jared L. Johnson, Tomer M. Yaron, Lewis C. Cantley, Michael B. Yaffe, Benjamin E. Turk, Emily M. Huntsman, Peter V. Hornbeck. An atlas of substrate specificities for the human tyrosine kinome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3487.