Gene Regulation, Stems Cells and Cancer

GO BACK

Gene Regulation and Signalling



GROUP LEADER:
Susana de la Luna (ICREA Research Professor)
POSTDOCTORAL FELLOWS:
Esteban Rozen (CIBERER Researcher)
PhD STUDENTS:
Laura Barba, Jacopo Boni (from October), Julia Rowenstrunk
LAB TECHNICIANS:
Chiara Di Vona, Alicia Raya

Summary


Figure 1

DYRK (dual-specificity tyrosine-regulated kinases) family members are found in four of the five main taxa (animalia, plantae, fungi and protista), and all them share common structural and biochemical properties. The mammalian DYRKs (DYRK1A, DYRK1B, DYRK2, DYRK3 and DYRK4) participate in signalling pathways critical for developmental processes and cell homeostasis. In particular, DYRK1A plays a key role in brain development. Both its overexpression, as part of the Down syndrome critical region, as well as its haploinsufficiency (OMIM 614104) are linked to neurodevelopmental alterations in humans. Our group is interested in understanding the biological roles of DYRK kinases, how they are regulated and how their activity impacts on gene regulatory processes.

Progress during 2014 includes the identification of a novel role for class I DYRKs as transcriptional activators. We found DYRK1A associated to the proximal promoter regions of a subset of growth-related genes characterized by the presence of a conserved palindromic motif. The results of biochemical and functional experiments are consistent with DYRK1A being a transcriptional regulator by acting as a RNA polymerase II CTD kinase (Figure 1).

A collaborative project has also revealed a novel mechanism for the control of NMDAR activity in neurons: DYRK1A phosphorylation of GluN2A at Ser1048 affects both the current density and gating of NMDA receptors.


Research Projects

  • Identification of regulatory mechanisms for DYRK kinases activity: allosteric regulation, protein stability, and expression.
  • Functional characterization of the nuclear activity of class I DYRKs.
  • Identification of chromatin targets of DYRK1A (collaboration with the groups of Stephan Ossowski, CRG, and of Nuria López-Bigas, UPF).
  • Characterization of the molecular mechanism that underlies the activity of DYRK1A as a transcriptional regulator: RNA polymerase II CTD phosphorylation.
  • Role of DYRKs as regulators of the activity of the NFAT transcription factors in calcineurin-dependent signaling pathways.
  • DYRK1A as a regulator of NMDA receptors (collaboration with the group of Xavier Altafaj, IDIBELL).
  • Role of amino acid repeat expansions in the functional diversification of duplicated transcription factors (collaboration with the group of M. Mar Albà, GRIB).

Selected Publications

Grau C, Arato K, Fernandez-Fernandez JM, Valderrama A, Sindreu C, Fillat C, Ferrer I, de la Luna S and Altafaj X.
“DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors.”
Front Cell Neurosci, 8:331 (2014).

Di Vona C, Bezdan D, Islam AB, Salichs E, Lopez-Bigas N, Ossowski S and de la Luna S.
“Chromatin-wide Profiling of DYRK1A Reveals a Role as a Gene-Specific RNA Polymerase II CTD Kinase.”
Mol Cell, in press. 10.1016/j.molcel.2014.12.026.