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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.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins. Heterogeneous nuclear ribonucleoprotein D-like (HNRPDL) is a member of this family. Though aberrant expression of HNRPDL has been reported in a few cancers, whether HNRPDL is deregulated in colon cancer patients and what role this protein plays in these cells are not known yet. In this study, we found that HNRPDL was significantly up-regulated in colon cancer specimens than control. We also demonstrated that HNRPDL silencing inhibited the growth of SW620 cells both in vitro and in vivo. Conversely, we constructed a retroviral vector to deliver HNRPDL into non-malignant NIH-3T3 cells and injected these cells into nude mice. HNRPDL-overexpressing NIH-3T3 cells generated tumors in nude mice but not the control cells. Mechanistically, HNRPDL promoted cell-cycle progression associated with enhanced expressions of cyclin D3 and Ki-67 but decreased expressions of p53 and p21. Taken together, our data demonstrate that HNRPDL is aberrantly expressed in colon cancer cells, which promotes the growth of these cells by activating cell-cycle progression.

Effectively detecting pH changes plays a critical role in exploring cellular functions and determining physiological and pathological processes. A novel ratiometric pH probe based on a glycopolymer, armored with properties of serum-stability, tumor-targeting, and pH monitoring, is designed. Random copolymers of 2-(methacrylamido) glucopyranose and fluorescein O-methacrylate are first synthesized by reversible addition fragmentation chain transfer polymerization. Acryloxyethyl thiocarbamoyl rhodamine B is then attached to the polymer chain to prepare ratiometric fluorescent pH probes via a thiol-ene reaction. The synthesized polymeric probes are characterized by NMR, gel permeation chromatography, UV-vis spectroscopy, and transmission electron microscopy, and the fluorescence responses are examined in phosphate buffer at different pHs. The cytotoxicity and confocal imaging experiments of the probes are detected using HeLa cells, demonstrating a low toxicity and superior biocompatibility for detecting pH changes in bioapplications.