This previous evidence for dynamic clusters of signaling factors, coupled with the observation that insulin receptor can be seen as puncta when visualized in live cells, led us to investigate whether insulin signaling involves dynamic clustering and whether dysregulation of such clustering contributes to insulin resistance. In addition, the dynamic properties of condensates have been shown to correlate with the activity and function of the molecules within the condensates 28, 31, 35, 36, 37, 38.
The terminal components of the Wnt, Lif, and TGFb developmental signaling pathways are directed to key developmental genes through integration into transcriptional condensates at those genes 26. For example, evidence suggests that T-cell receptor activation causes the formation of condensate compartments at the plasma membrane that incorporate signaling components and promote signaling 24, 25, and similar observations were recently reported for various RTKs 30. Condensate formation and condensate properties have been shown to contribute to diverse types of cellular signaling 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. Biomolecular condensates are cellular compartments wherein proteins and nucleic acids concentrate without being physically delimitated by a membrane 34. Recent reports indicate that signaling factors can form dynamic clusters with properties and characteristics expected of biomolecular condensates 24, 25, 26, 27, 28, 29, 30, 31, 32, 33. These include alterations in insulin signaling components as a consequence of chronic hyperinsulinemia, nutritional excess, inflammation, oxidative stress, ER stress, fatty acid accumulation, and mitochondrial dysfunction 1, 2, 17, 18, 20, 21, 22, 23. Multiple cell-extrinsic and cell-intrinsic factors can blunt the cellular response to insulin and thus contribute to insulin resistance 1, 2, 19.
Insulin resistance is a heterogeneous disorder common to type 2 diabetes (T2D), obesity, and metabolic syndrome 17, 18. The active IR is internalized by endocytosis and is either degraded in lysosomes, recycled back to the plasma membrane, or transported into the nucleus where it becomes associated with insulin-responsive genes 10, 11, 12, 13, 14, 15, 16. These pathways regulate glucose uptake, lipogenesis, gluconeogenesis, glycogen synthesis, and cellular proliferation 1, 2, 9.
Insulin binding induces IR autophosphorylation and IR phosphorylation of IR substrate (IRS) and src homology 2 (SHC) proteins, which activate PI3K-AKT and ERK signaling, respectively 1, 2, 3, 4, 5, 6, 7, 8. Insulin binds at the cell surface to the insulin receptor (IR), a receptor tyrosine kinase (RTK) 3, 4. Insulin signaling controls cell growth and metabolism, and dysregulation of this pathway is a common feature of type 2 diabetes (T2D), obesity, and metabolic syndrome 1, 2. Nature Communications volume 13, Article number: 7522 ( 2022) The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
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