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PTPN11 induces endoplasmic stress and apoptosis in SH-SY5Y cells

Nitin Chitranshi¹, Yogita Dheer¹, Veer Gupta²

¹Faculty of Medicine and Health Sciences, Macquarie University, F10A, 2 Technology Place, North Ryde, NSW 2109, Australia.

|September 27, 2017

Abstract:

PTPN11 is associated with regulation of growth factor signaling pathways in neuronal cells. Using SH-SY5Y neuroblastoma cells, we showed that adeno-associated virus (AAV)-mediated PTPN11 upregulation was associated with TrkB antagonism, reduced neuritogenesis and enhanced endoplasmic reticulum (ER) stress response leading to apoptotic changes. Genetic knock-down of PTPN11 on the other hand leads to increased TrkB phosphorylation in SH-SY5Y cells. ER stress response induced by PTPN11 upregulation was alleviated pharmacologically by a TrkB agonist. Conversely the enhanced ER stress response induced by TrkB receptor antagonism was ameliorated by PTPN11 suppression, providing evidence of cross-talk of PTPN11 effects with TrkB actions. BDNF treatment of neuronal cells with PTPN11 upregulation also resulted in reduced expression of ER stress protein markers. This study provides evidence of molecular interactions between PTPN11 and the TrkB receptor in SH-SY5Y cells. The results reinforce the role played by PTPN11 in regulating neurotrophin protective signaling in neuronal cells and highlight that PTPN11 dysregulation promotes apoptotic activation. Based on these findings we suggest that blocking PTPN11 could have potential beneficial effects to limit the progression of neuronal loss in neurodegenerative disorders.

Insights

PTPN11 protein dysregulation promotes neuronal apoptosis by interfering with TrkB signaling. Blocking PTPN11 may offer neuroprotection in neurodegenerative diseases.

Area of Science:

Neuroscience
Molecular Biology
Cell Biology

Background:

PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) plays a role in growth factor signaling.
Dysregulation of PTPN11 is implicated in cellular processes relevant to neuronal function.

Purpose of the Study:

To investigate the molecular interactions between PTPN11 and the TrkB receptor signaling pathway.
To determine the impact of PTPN11 modulation on neuronal stress responses and apoptosis.

Main Methods:

Utilized SH-SY5Y neuroblastoma cells.
Employed adeno-associated virus (AAV)-mediated gene manipulation (upregulation and knockdown) of PTPN11.
Assessed TrkB phosphorylation, neuritogenesis, endoplasmic reticulum (ER) stress markers, and apoptotic changes.
Investigated effects of pharmacological TrkB agonism and PTPN11 suppression.

Main Results:

PTPN11 upregulation in SH-SY5Y cells led to TrkB antagonism, reduced neuritogenesis, and increased ER stress and apoptosis.
PTPN11 knockdown resulted in increased TrkB phosphorylation.
Pharmacological TrkB agonism alleviated ER stress induced by PTPN11 upregulation.
PTPN11 suppression ameliorated ER stress caused by TrkB antagonism, indicating cross-talk.
BDNF treatment reduced ER stress markers in cells with PTPN11 upregulation.

Conclusions:

PTPN11 directly interacts with the TrkB receptor pathway in neuronal cells.
PTPN11 dysregulation promotes neuronal apoptosis via disruption of neurotrophin signaling.
Targeting PTPN11 inhibition presents a potential therapeutic strategy for neurodegenerative disorders by limiting neuronal loss.

Read full analysis

Keywords:

PTPN11 TrkB apoptosis brain-derived neurotrophic factor phosphatase phosphorylation

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