Tribbles Homolog 3, or TRB3, is a protein involved in various bodily processes. It is recognized as a pseudokinase, a protein with a similar structure to kinases but lacking their direct enzymatic activity. Instead of directly adding phosphate groups, TRB3 often acts as a scaffold or regulator, influencing the activity of other proteins. This protein was initially identified as a gene upregulated in response to cellular stress, highlighting its involvement in cellular stress responses.
Understanding TRB3’s Cellular Roles
TRB3 functions by interacting with and modulating other proteins. Its pseudokinase domain serves as a binding platform for cellular components. This allows TRB3 to influence different signaling pathways without directly phosphorylating targets.
TRB3 is involved in cellular stress responses, such as endoplasmic reticulum (ER) stress and oxidative stress. When cells experience these stresses, TRB3 expression increases, indicating its role in the adaptive response. TRB3 also participates in regulating protein degradation pathways, including the proteasome system, which breaks down unneeded or damaged proteins.
TRB3’s influence extends to major signaling pathways like AKT/PKB and NF-κB. It can bind to and regulate the activity of proteins within these pathways, thus impacting processes like cell survival, inflammation, and cell differentiation. Its ability to form protein-protein interactions allows it to act as a junction for several signaling cascades.
TRB3’s Impact on Metabolic Health
TRB3 is strongly associated with metabolic health, particularly insulin resistance and Type 2 Diabetes. Elevated TRB3 levels are observed in conditions with altered blood sugar, including in human and mouse pancreatic islets. TRB3 interferes with insulin signaling by inhibiting proteins like AKT, a significant component in glucose uptake and metabolism.
By binding to AKT, TRB3 prevents its activation. This inhibition disrupts the insulin signaling pathway, leading to reduced glucose uptake by cells and contributing to insulin resistance. Research indicates that TRB3 expression in the liver increases in diabetic animal models, supporting its role in insulin resistance.
TRB3 is also implicated in lipid metabolism. It is linked to fatty liver disease (hepatic steatosis). Insulin resistance is common in non-alcoholic fatty liver disease patients, and TRB3’s role in blocking insulin signaling suggests its involvement. Studies show TRB3 is upregulated in animal models of metabolic diseases, including obesity and hyperglycemia.
TRB3 in Cancer and Neurodegenerative Conditions
TRB3’s role extends to cancer and neurodegenerative conditions, often with complex, context-dependent effects. In cancer, TRB3 can have dual roles, promoting cell survival or encouraging cell death depending on the cancer type and cellular environment. It is noted in various cancers, including breast, prostate, and liver cancer.
Its influence on cell death and stress responses contributes to its complex actions in tumor development. Research continues into TRB3’s contributions to tumorigenesis. The unique structure of TRB3, as a pseudokinase, provides an opportunity for drug design in cancer therapy.
TRB3 also connects to neurodegenerative diseases like Alzheimer’s and Parkinson’s. In Parkinson’s disease, TRB3 levels are elevated in specific neurons in patients and cellular models. Overexpression of TRB3 promotes neuronal death, while reducing its levels protects neurons from damage in these models. TRB3 interacts with Parkin, a protein linked to neuronal survival; elevated TRB3 can reduce Parkin expression, contributing to neuronal death in Parkinson’s disease. This highlights TRB3 as a target for therapies to slow neuron degeneration.