The Discoidin domain receptor 1 gene has a functional A2RE sequence

Abstract

J. Neurochem. (2012) 120, 408–418. Abstract Discoidin domain receptor 1 (DDR1) is expressed in myelin oligodendrocytes and co‐localizes with myelin basic protein (MBP). Alternative splicing of DDR1 generates five isoforms designated DDR1a–e. The MBP mRNA contains an hnRNP A2 response element (A2RE) sequence that is recognized by heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, which is responsible for transport of the MBP mRNA to oligodendrocyte processes. We hypothesized that DDR1 could have a functional A2RE sequence. By in silico analysis, we identified an A2RE‐like sequence in the human DDR1 mRNA. We observed nuclear and dendrite cytoplasmic immunofluorescence, indicating that DDR1 and hnRNP A2/B1 co‐localize in human oligodendrocytes and in differentiated HOG16 cells. The A2RE‐like sequence of DDR1 contains the single nucleotide polymorphism rs2267641, and we found that in the human brain, the minor allele is associated with lower and higher levels DDR1b and DDR1c mRNA expression, respectively. Moreover, a positive correlation between DDR1c and the myelin genes myelin‐associated glycoprotein and oligodendrocyte lineage transcription factor 2 was found. Differentiated HOG16 cells transfected with an hnRNP A2/B1 siRNA simultaneously show a decrease and an increase in the DDR1c and DDR1b mRNA expression levels, respectively, which was accompanied by a decrease in DDR1 protein levels at the cytoplasmic edges. These results suggest that the DDR1 A2RE sequence is functionally involved in the hnRNP A2/B1‐mediated splicing and transport of the DDR1c mRNA.

Discoidin Domain Receptor Functions in Physiological and Pathological Conditions

“…Likewise, the DNA repair protein XRCC3, which is induced by genotoxic stress, can up-regulate DDR1 expression (Martinez-Marignac et al, 2011). The DDR1 gene also contains a hnRNP A2 response element sequence, which may be involved in alternative splicing and nuclear export of DDR1 mRNA in oligodendrocytes (Roig et al, 2012). DDR1 expression is downregulated during induction of epithelial-mesenchymal transition (EMT).…”

The roles of hnRNP A2/B1 in RNA biology and disease

“…A2‐mediated RNA transport is specific to an A2RE or A2RE‐like motif, which can be found in a large number of RNAs, such as the mRNA of MBP (Makeyev & Liebhaber, 2002), CaMKII (Ca2+/calmodulin‐dependent protein kinase II, Arc (activity‐regulated cytoskeleton‐associated protein), neurogranin (Gao, Tatavarty, Korza, Levin, & Carson, 2008), MAP2A, GABA receptor α (Munro et al, 1999), and Discoidin domain receptor 1 (Roig, Moyano, Martorell, Costas, & Vilella, 2012). However, the A2 protein also mediates noncanonical motif transport pathways.…”

Discoidin domain receptor tyrosine kinases: new players in cancer progression

“…Similarly, overexpression of the DNA repair protein XRCC3, results in DDR1 upregulation by an as yet unknown mechanism [73]. A recent study in oligodendrocytes found that the DDR1 gene contains an hnRNP A2 response element-like sequence, which may be involved in alternative splicing and nuclear export of DDR1 mRNA [74]. Also, DDR1 mRNA is a direct target of the microRNA miR-199a-5p; levels of miR-199a-5p inversely correlate with DDR1 expression in human hepatocellular carcinoma cells [75].…”