PTPRJ is a negative regulator of insulin signaling in neuronal cells, impacting protein biosynthesis, and neurite outgrowth.
Jannis UlkeSimran ChopraOtsuware Linda-Josephine KadiriPeter GeserickVanessa SteinSahar CheshmehAndré KleinriddersKai KappertPublished in: Journal of neuroendocrinology (2024)
Central insulin resistance has been linked to the development of neurodegenerative diseases and mood disorders. Various proteins belonging to the enzyme family of protein tyrosine phosphatases (PTPs) act as inhibitors of insulin signaling. Protein tyrosine phosphatase receptor type J (PTPRJ) has been identified as a negative regulator in insulin signaling in the periphery. However, the impact of PTPRJ on insulin signaling and its functional role in neuronal cells is largely unknown. Therefore, we generated a Ptprj knockout (KO) cell model in the murine neuroblast cell line Neuro2a by CRISPR-Cas9 gene editing. Ptprj KO cells displayed enhanced insulin signaling, as shown by increased phosphorylation of the insulin receptor (INSR), IRS-1, AKT, and ERK1/2. Further, proximity ligation assays (PLA) revealed both direct interaction of PTPRJ with the INSR and recruitment of this phosphatase to the receptor upon insulin stimulation. By RNA sequencing gene expression analysis, we identified multiple gene clusters responsible for glucose uptake and metabolism, and genes involved in the synthesis of various lipids being mainly upregulated under PTPRJ deficiency. Furthermore, multiple Ca 2+ transporters were differentially expressed along with decreased protein biosynthesis. This was accompanied by an increase in endoplasmic reticulum (ER) stress markers. On a functional level, PTPRJ deficiency compromised cell differentiation and neurite outgrowth, suggesting a role in nervous system development. Taken together, PTPRJ emerges as a negative regulator of central insulin signaling, impacting neuronal metabolism and neurite outgrowth.
Keyphrases
- type diabetes
- glycemic control
- induced apoptosis
- insulin resistance
- cell cycle arrest
- single cell
- signaling pathway
- transcription factor
- protein protein
- amino acid
- cell proliferation
- stem cells
- adipose tissue
- high throughput
- protein kinase
- cell therapy
- metabolic syndrome
- endoplasmic reticulum stress
- gene expression
- blood glucose
- bipolar disorder
- depressive symptoms
- cell death
- genome wide identification
- blood pressure
- bone marrow
- physical activity
- cerebral ischemia
- genome wide
- pi k akt
- subarachnoid hemorrhage
- replacement therapy
- genome editing