An atlas of substrate specificities for the human serine/threonine kinome

Jared L. Johnson, Tomer M. Yaron, Emily M. Huntsman, Alexander Kerelsky, Junho Song, Amit Regev, Ting-Yu Lin, Katarina Liberatore, Daniel M. Cizin, Benjamin M. Cohen, Neil Vasan, Yilun Ma, Konstantin Krismer, Jaylissa Torres Robles, Bert Kooij, Anne E. Vlimmeren, Nicole Andrée-Busch, Norbert F. Käufer, Maxim V. Dorovkov, Alexey G. Ryazanov, Yuichiro Takagi, Edward R. Kastenhuber, Marcus D. Goncalves, Benjamin D. Hopkins, Olivier Elemento, Dylan J. Taatjes, Alexandre Maucuer, Akio Yamashita, Alexei Degterev, Mohamed Uduman, Jingyi Lu, Sean D. Landry, Bin Zhang, Ian Cossentino, Rune Linding, John Blenis, Peter V. Hornbeck, Benjamin E. Turk (), Michael B. Yaffe () and Lewis C. Cantley ()
Additional contact information
Jared L. Johnson: Weill Cornell Medicine
Tomer M. Yaron: Weill Cornell Medicine
Emily M. Huntsman: Weill Cornell Medicine
Alexander Kerelsky: Weill Cornell Medicine
Junho Song: Weill Cornell Medicine
Amit Regev: Weill Cornell Medicine
Ting-Yu Lin: Weill Cornell Medicine
Katarina Liberatore: Weill Cornell Medicine
Daniel M. Cizin: Weill Cornell Medicine
Benjamin M. Cohen: Weill Cornell Medicine
Neil Vasan: Columbia University Irving Medical Center
Yilun Ma: Weill Cornell Medicine
Konstantin Krismer: Massachusetts Institute of Technology
Jaylissa Torres Robles: Yale School of Medicine
Bert Kooij: Massachusetts Institute of Technology
Anne E. Vlimmeren: Massachusetts Institute of Technology
Nicole Andrée-Busch: Technische Universität Braunschweig
Norbert F. Käufer: Technische Universität Braunschweig
Maxim V. Dorovkov: Rutgers Robert Wood Johnson Medical School
Alexey G. Ryazanov: Rutgers Robert Wood Johnson Medical School
Yuichiro Takagi: Indiana University School of Medicine
Edward R. Kastenhuber: Weill Cornell Medicine
Marcus D. Goncalves: Weill Cornell Medicine
Benjamin D. Hopkins: Icahn School of Medicine at Mount Sinai
Olivier Elemento: Weill Cornell Medicine
Dylan J. Taatjes: University of Colorado
Alexandre Maucuer: Univ Evry, INSERM U1204, Université Paris-Saclay
Akio Yamashita: University of the Ryukyus
Alexei Degterev: Tufts University School of Medicine
Mohamed Uduman: Cell Signaling Technology
Jingyi Lu: Cell Signaling Technology
Sean D. Landry: Cell Signaling Technology
Bin Zhang: Cell Signaling Technology
Ian Cossentino: Cell Signaling Technology
Rune Linding: Humboldt-Universität zu Berlin
John Blenis: Weill Cornell Medicine
Peter V. Hornbeck: Cell Signaling Technology
Benjamin E. Turk: Yale School of Medicine
Michael B. Yaffe: Massachusetts Institute of Technology
Lewis C. Cantley: Weill Cornell Medicine

Nature, 2023, vol. 613, issue 7945, 759-766

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-022-05575-3

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