Investigation of PTPN21 in ErbBs signaling transduction and its potential biological function

Abstract

The Neuregulin-3 (NRG3) is a vital neurotrophic factor in neurogenesis and promotes neuronal survival. In order to detect regulators of NRG3, expression quantitative trait locus (eQTL) analysis on recombinant inbred mouse brain was performed and identified protein tyrosine phosphatase non-receptor 21 (Ptpn21) as a novel mediator of Nrg3. Our study unveils the mechanism between PTPN21 that leads to enhancement of NRG3 transcription and demonstrates biological function of PTPN21 in neuronal survival. Our studies support activation of Elk-1 by PTPN21 was abolished by dominant negative Ras mutant (N17S) or MEK inhibitor U0126. Furthermore, a novel Elk-1 binding motif was identified in a region located ~1919 bp upstream of NRG3 initiation codon.

PTPN21’s signal induction power comes up upstream of Ras with one of the RTK receptors, therefore tagged reciprocal co-immunoprecipitation was carried out to confirms PTPN21 interacts with a RTK receptor - ErbB4. Furthermore, PTPN21 positively induces ErbB1/4 activity revealed by immunoblotting and via monitoring activity and phosphorylation levels of downstream transcription factor, such as Elk-1 and STAT5. It is also shown that PTPN21 stabilizes not just ErbB4 but also other members of the ErbB family of receptors.

PTPN21’s neuronal biological relevance is also characterized by its ability to enhance neuronal survival, a time-course trophic factor deprivation assay demonstrated that PTPN21 promotes cortical neurons survival in a manner similar to pro-cell survival protein, NRG3 and activated Elk-1. While PTPN21 also reduces PS1 protein levels through Elk-1 transcription factor. In summary, the author identified the PTPN21 interacting with a RTK receptor and enhance downstream signaling, NRG3 gene as a novel target for Elk-1 transcription factor and characterized the role of PTPN21 in relation to the activation of Elk-1, hence the expression of NRG3 and consequently promoting cortical neuronal survival. Much more research is needed to illuminate this thus-far loosely defined, but complex relationship.