DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1

J Biol Chem. 2010 Apr 23;285(17):13223-32. doi: 10.1074/jbc.M110.102574. Epub 2010 Feb 18.

Abstract

DYRK1A (the dual specificity tyrosine phosphorylation-regulated kinase 1A) plays an important role in body growth and brain physiology. Overexpression of this kinase has been associated with the development of Down syndrome in both human and animal models, whereas single copy loss-of-function of DYRK1A leads to increased apoptosis and decreased brain size. Although more than a dozen of DYRK1A targets have been identified, the molecular basis of its involvement in neuronal development remains unclear. Here we show that DYRK1A and another pro-survival member of the DYRK family, DYRK3, promote cell survival through phosphorylation and activation of SIRT1, an NAD(+)-dependent protein deacetylase that is essential in a variety of physiological processes including stress response and energy metabolism. DYRK1A and DYRK3 directly phosphorylate SIRT1 at Thr(522), promoting deacetylation of p53. A SIRT1 phosphorylation mimetic (SIRT1 T522D) displays elevated deacetylase activity, thus inhibiting cell apoptosis. Conversely, a SIRT1 dephosphorylation mimetic (SIRT1 T522V) fails to mediate DYRK-induced deacetylation of p53 and cell survival. We show that knockdown of endogenous DYRK1A and DYRK3 leads to hypophosphorylation of SIRT1, sensitizing cells to DNA damage-induced cell death. We also provide evidence that phosphorylation of Thr(522) activates SIRT1 by promoting product release, thereby increasing its enzymatic turnover. Taken together, our findings provide a novel mechanism by which two anti-apoptotic DYRK members promote cell survival through direct modification of SIRT1. These findings may have important implications in understanding the molecular mechanisms of tumorigenesis, Down syndrome, and aging.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylation
  • Aging / genetics
  • Aging / metabolism
  • Amino Acid Substitution
  • Animals
  • Apoptosis / genetics
  • Brain / enzymology
  • Brain / pathology
  • Cell Line
  • Cell Survival / genetics
  • DNA Damage / genetics
  • Disease Models, Animal
  • Down Syndrome / enzymology*
  • Down Syndrome / genetics
  • Down Syndrome / pathology
  • Dyrk Kinases
  • Enzyme Activation / genetics
  • Humans
  • Mice
  • Mutation, Missense
  • Organ Size / genetics
  • Phosphorylation / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • DYRK3 protein, human
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • SIRT1 protein, human
  • Sirt1 protein, mouse
  • Sirtuin 1