DYRK1A controls the transition from proliferation to quiescence during lymphoid development by destabilizing Cyclin D3

J Exp Med. 2015 Jun 1;212(6):953-70. doi: 10.1084/jem.20150002. Epub 2015 May 25.


Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells' proliferation, but little is known about its posttranslational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition in mice, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a nonphosphorylatable Cyclin D3 T283A mutant recapitulated these defects, whereas inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition or loss. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • B-Lymphocytes / cytology
  • Bone Marrow Cells / cytology
  • Cell Proliferation
  • Cyclin D3 / metabolism*
  • E2F Transcription Factors / metabolism
  • Exons
  • Female
  • Flow Cytometry
  • Gene Library
  • Genotype
  • HEK293 Cells
  • Humans
  • Lymphopoiesis*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction
  • T-Lymphocytes / cytology
  • Transcription, Genetic


  • Ccnd3 protein, mouse
  • Cyclin D3
  • E2F Transcription Factors
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases