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Journal Articles Nature Year : 2023

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

Jared L Johnson
Tomer M Yaron
Emily M Huntsman
  • Function : Author
Alexander Kerelsky
  • Function : Author
Junho Song
Amit Regev
  • Function : Author
Ting-Yu Lin
  • Function : Author
Katarina Liberatore
  • Function : Author
Daniel M Cizin
  • Function : Author
Benjamin M Cohen
  • Function : Author
Neil Vasan
  • Function : Author
Yilun Ma
  • Function : Author
Konstantin Krismer
Jaylissa Torres Robles
Bert van de Kooij
  • Function : Author
Anne E van Vlimmeren
Nicole Andrée-Busch
  • Function : Author
Norbert F Käufer
  • Function : Author
Maxim V Dorovkov
Alexey G Ryazanov
  • Function : Author
Yuichiro Takagi
Edward R Kastenhuber
Marcus D Goncalves
Benjamin D Hopkins
  • Function : Author
Olivier Elemento
  • Function : Author
Dylan J Taatjes
Akio Yamashita
  • Function : Author
Alexei Degterev
Mohamed Uduman
  • Function : Author
Jingyi Lu
  • Function : Author
Sean D Landry
Bin Zhang
  • Function : Author
Ian Cossentino
Rune Linding
  • Function : Author
John Blenis
Peter V Hornbeck
  • Function : Author
Benjamin E Turk
Michael B Yaffe
Lewis C Cantley

Abstract

Abstract Protein phosphorylation is one of the most widespread post-translational modifications in biology 1,2 . 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 processes 3,4 . 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 responsible 3 . 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.

Dates and versions

hal-04231548 , version 1 (10-10-2023)

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Jared L Johnson, Tomer M Yaron, Emily M Huntsman, Alexander Kerelsky, Junho Song, et al.. An atlas of substrate specificities for the human serine/threonine kinome. Nature, 2023, 613 (7945), pp.759-766. ⟨10.1038/s41586-022-05575-3⟩. ⟨hal-04231548⟩
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