PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling

• Published in: The international journal of biochemistry & cell biology Vol. 61; pp. 53 - 62
• Main Authors: Plani-Lam, Janice Hiu-Chor, Chow, Tai-Cheong, Siu, Kam-Leung, Chau, Wing Hin, Ng, Ming-Him James, Bao, Suying, Ng, Cheung Toa, Sham, Pak, Shum, Daisy Kwok-Yan, Ingley, Evan, Jin, Dong-Yan, Song, You-Qiang
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.04.2015
• Subjects: Animals; Cell Survival - physiology; Cerebral Cortex - cytology; Cerebral Cortex - metabolism; ErbB4; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neuregulins - biosynthesis; Neuregulins - genetics; Neuregulins - metabolism; Neurites - metabolism; Neuritic elongation; Neurons - cytology; Neurons - metabolism; NRG3; Pro-neuronal survival; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; PTPN21; Quantitative Trait Loci; Receptor, ErbB-4 - genetics; Receptor, ErbB-4 - metabolism; Signal Transduction; Transfection; GWAS; ErbB4; IP; Pro-neuronal survival; RTK; PTPN21; eQTL; p-Tyr; FAK; NRG3; Elk-1; Neuritic elongation; SNPs; KIF1C; Etk; RT-qPCR
• ISSN: 1357-2725; 1878-5875
• DOI: 10.1016/j.biocel.2015.02.003

•Linking NRG3 and PTPN21 within one signaling cascade.•Identified ErbB4 as a novel binding partner of PTPN21.•PTPN21 promotes stability of ErbB4 and consequently induces its downstream signaling.•Identified Elk-1 as the novel transcription factor which regulates NRG3.•Biologically, PTPN21 positively influences cortical neuronal survival and enhances neuritic length in a similar manner to Elk-1. Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene–gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and Nrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21–NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.