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Mol. Cell. Biol. doi:10.1128/MCB.00394-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Sprouty2 inhibitory activity on FGF-signaling is modulated by the protein kinase DYRK1A

Genes and Disease Program, Centre for Genomic Regulation (CRG), UPF, Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER-ISCIII), Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

^* To whom correspondence should be addressed. Email: susana.luna{at}crg.es.

	Abstract

Raf-MEK-Erk (MAPK) signaling initiated by growth factor-engaged receptor tyrosine kinases (RTK) is modulated by an intricate network of positive and negative feedback loops which determine the specificity and spatio-temporal characteristics of the intracellular signal. Well-known antagonists of RTK signaling are the Sprouty proteins. The activity of Sprouty proteins is modulated by phosphorylation. However, little is known about the kinases responsible for these post-translational modifications. We identify DYRK1A as one of the protein kinases of Sprouty2. We show that DYRK1A interacts with, and regulates the phosphorylation status of Sprouty2. Moreover, we identify Thr75 on Sprouty2 as a DYRK1A phosphorylation site in vitro and in vivo. This site is functional, since its mutation enhanced the repressive function of Sprouty2 on FGF-induced Erk signaling. Further supporting a functional interaction, DYRK1A and Sprouty2 are present in protein complexes in mouse brain, where their expression overlaps in several structures. Moreover, both proteins co-purify with the synaptic plasma membrane fraction of a crude synaptosomal preparation, and co-localized in growth cones, pointing to a role in nerve terminals. Our results suggest therefore that DYRK1A positively regulates FGF-MAPK signaling by phosphorylation-dependent impairment of the inhibitory activity of Sprouty2.