Gene regulation and signaling

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, and their dysregulation has been linked to disease in humans. In the case of DYRK1A, both its overexpression, as part of the Down syndrome critical region, as well as its haploinsufficiency are linked to clinical phenotypes in humans. Our group is interested in understanding the biological roles of DYRK kinases, how they are regulated and which are the mechanisms underlying their connection to disease.

Progress during 2018 has focused mostly on DYRK1A. We have associated a novel biological role to DYRK1A as a critical regulator of VEGF/calcium/NFAT signalling in angiogenesis. In addition, we have established a link between DYRK1A overexpression and pancreatic ductal adenocarcinoma and provide evidence on the kinase as a possible therapeutic target in this cancer type. Both studies have highlighted an activity of DYRK1A as a regulator of the stability of receptor tyrosine kinases (VEGFR2, c-MET) in different physiological contexts.

• Identification of regulatory mechanisms for DYRK kinases activity: allosteric regulation, protein stability, expression.
• Characterization of the molecular mechanism that underlies the activity of DYRK class I as transcriptional regulators.
• Definition of the interactome of class I DYRKs.
• Role of DYRKs as regulators of the activity of the NFAT transcription factors in calcineurin-dependent signalling pathways.
• Characterization of DYRK1A missense mutations in DYRK1A haploinsufficiency syndrome
• Exploring DYRKs as potential targets in cancer.

Rozen EJ, Roewenstrunk J, Barallobre MJ, Di Vona C, Jung C, Figueiredo AF, Luna J, Fillat C, Arbones ML, Graupera M, Valverde MA and de la Luna S.
“DYRK1A kinase positively regulates angiogenic responses in endothelial cells.”
Cell Rep 23, 1867-1878, 2018.

Luna J, Boni J, Cuatrecasas M, Bofill-De Ros X, Nunez-Manchon E, Gironella M, Vaquero EC, Arbones ML, de la Luna S* and Fillat C*.
“DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth.”
Gut, gutjnl-2018-316128, 2018.
*senior & corresponding co-authors.