Abstract
Dual specificity tyrosine phosphorylation regulated kinase 1A, DYRK1A, functions in multiple cellular pathways, including signaling, endocytosis, synaptic transmission, and transcription. Alterations in dosage of DYRK1A leads to defects in neurogenesis, cell growth, and differentiation, and may increase the risk of certain cancers. DYRK1A localizes to a number of subcellular structures including vesicles where it is known to phosphorylate a number of proteins and regulate vesicle biology. However, the mechanism by which it translocates to vesicles is poorly understood. Here we report the discovery of TRAF2, an E3 ligase, as an interaction partner of DYRK1A. Our data suggest that TRAF2 binds to PVQE motif residing in between the PEST and histidine repeat domain (HRD) of DYRK1A protein, and mediates K63-linked ubiquitination of DYRK1A. This results in translocation of DYRK1A to the vesicle membrane. DYRK1A increases phosphorylation of Sprouty 2 on vesicles, leading to the inhibition of EGFR degradation, and depletion of TRAF2 expression accelerates EGFR degradation. Further, silencing of DYRK1A inhibits the growth of glioma cells mediated by TRAF2. Collectively, these findings suggest that the axis of TRAF2–DYRK1A-Sprouty 2 can be a target for new therapeutic development for EGFR-mediated human pathologies.
Highlights
Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is a member of the CMGC (including cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases) group of serine/threonine kinases [1]
Among the novel interactions of DYRK1A, 36–48 h of transfection of plasmids as indicated using PEI or Lipofectamine we found TRAF2, an E3 ubiquitin ligase for both K48- and K63
Understandings of DYRK1A functions has steadily increased in the past two decades and we currently know more than 20 substrates that can be phosphorylated by DYRK1A in various cellular compartments
Summary
Dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is a member of the CMGC (including cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases) group of serine/threonine kinases [1]. Growth retardation and a small brain phenotype is observed due to loss of DYRK1A homologs in Drosophila and zebrafish [8, 9]. DYRK1A is shown to phosphorylate several proteins involved in neuronal synaptic transmission, including Dynamin 1, Amphiphysin 1, and Synaptojanin 1 [2, 11,12,13,14], and functions in synaptic vesicle endocytosis [11]. Overall, these studies indicate a function of DYRK1A in neuronal development
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