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 van de Kooij, Anne E. van Vlimmeren, Nicole Andrée-Busch, Norbert F. Käufer, Maxim V. Dorovkov, Alexey G. RyazanovYuichiro 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, Lewis C. Cantley

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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.

Original languageEnglish
Pages (from-to)759-766
Number of pages8
JournalNature
Volume613
Issue number7945
DOIs
StatePublished - 26 Jan 2023
Externally publishedYes

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Publisher Copyright:
© 2023, The Author(s).

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