The intrinsic substrate specificity of the human tyrosine kinome

Tomer M. Yaron-Barir, Brian A. Joughin, Emily M. Huntsman, Alexander Kerelsky, Daniel M. Cizin, Benjamin M. Cohen, Amit Regev, Junho Song, Neil Vasan, Ting-Yu Lin, Jose M. Orozco, Christina Schoenherr, Cari Sagum, Mark T. Bedford, R. Max Wynn, Shih-Chia Tso, David T. Chuang, Lei Li, Shawn S.-C. Li, Pau Creixell, Konstantin Krismer, Mina Takegami, Harin Lee, Bin Zhang, Jingyi Lu, Ian Cossentino, Sean D. Landry, Mohamed Uduman, John Blenis, Olivier Elemento, Margaret C. Frame, Peter V. Hornbeck, Lewis C. Cantley (), Benjamin E. Turk (), Michael B. Yaffe () and Jared L. Johnson ()
Additional contact information
Tomer M. Yaron-Barir: Weill Cornell Medicine
Brian A. Joughin: Massachusetts Institute of Technology
Emily M. Huntsman: Weill Cornell Medicine
Alexander Kerelsky: Weill Cornell Medicine
Daniel M. Cizin: Weill Cornell Medicine
Benjamin M. Cohen: Weill Cornell Medicine
Amit Regev: Weill Cornell Medicine
Junho Song: Weill Cornell Medicine
Neil Vasan: Columbia University Irving Medical Center
Ting-Yu Lin: Weill Cornell Medicine
Jose M. Orozco: Harvard Medical School
Christina Schoenherr: University of Edinburgh
Cari Sagum: The University of Texas MD Anderson Cancer Center
Mark T. Bedford: The University of Texas MD Anderson Cancer Center
R. Max Wynn: University of Texas Southwestern Medical Center
Shih-Chia Tso: University of Texas Southwestern Medical Center
David T. Chuang: University of Texas Southwestern Medical Center
Lei Li: University of Health and Rehabilitation Sciences
Shawn S.-C. Li: Western University
Pau Creixell: Massachusetts Institute of Technology
Konstantin Krismer: Massachusetts Institute of Technology
Mina Takegami: Massachusetts Institute of Technology
Harin Lee: Cell Signaling Technology
Bin Zhang: Cell Signaling Technology
Jingyi Lu: Cell Signaling Technology
Ian Cossentino: Cell Signaling Technology
Sean D. Landry: Cell Signaling Technology
Mohamed Uduman: Cell Signaling Technology
John Blenis: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Margaret C. Frame: University of Edinburgh
Peter V. Hornbeck: Cell Signaling Technology
Lewis C. Cantley: Weill Cornell Medicine
Benjamin E. Turk: Yale School of Medicine
Michael B. Yaffe: Massachusetts Institute of Technology
Jared L. Johnson: Weill Cornell Medicine

Nature, 2024, vol. 629, issue 8014, 1174-1181

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07407-y Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:629:y:2024:i:8014:d:10.1038_s41586-024-07407-y

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07407-y

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().