Insulin signaling is a highly dynamic network that integrates temporal and spatial cues to regulate metabolic and growth-related processes. Central to this system are the insulin receptor substrates (IRS1 and IRS2), which function as key adaptors that amplify signals, mediate feedback regulation, and facilitate crosstalk between pathways. The large (>1000 amino acid) unstructured C-terminal tail of IRS proteins serves as a critical information-processing hub, dictating the flow of signals within the insulin signaling network. Upon insulin stimulation, rapid tyrosine phosphorylation of IRS proteins activates PI3K and recruits other signal modifier. Beyond tyrosine phosphorylation, extensive serine/threonine (Ser/Thr) phosphorylation modulates IRS function, a process historically linked to insulin resistance but increasingly recognized as essential for normal insulin action.
Here, we hypothesize that Ser/Thr phosphorylation-driven negative feedback and crosstalk are essential for maintaining balance between the metabolic and mitogenic arms of insulin signaling. Disruption of these processes by stress kinase activation may represent a unifying mechanism underlying insulin resistance. Specifically, we predict that loss of normal negative feedback:
This presentation will highlight our recent findings that support these ideas. Using phosphoproteomics and live-cell imaging, we demonstrate that loss of Akt-mediated feedback onto IRS1/2 leads to aberrant PI3K-dependent ERK hyperactivation. This hyperactivation arises through three distinct mechanisms converging on the ERK pathway, revealing novel feedback-driven control points within the network. Furthermore, our preliminary data suggest that these alterations promote an insulin resistance phenotype under conditions that, based on current models, should be protective.
Rather than a simple linear cascade, insulin signaling operates as an intricate system that encodes and decodes biochemical inputs. IRS proteins, via their extensive post-translational modifications (PTMs) shape the overall signaling landscape. Normally, these phosphorylation events establish a finely tuned signature that directs cellular responses such as glucose uptake. However, under conditions of stress this phosphorylation landscape is perturbed. Consequently, the encoded information is misinterpreted, leading to maladaptive outcomes such as paradoxical hyperactivation of alternative pathways, a hallmark of insulin resistance.
These insights have the potential to reconcile disparate observations and competing hypotheses in the field, offering a cohesive framework for understanding the etiology of insulin resistance.By elucidating how IRS phosphorylation encodes information and how stress kinase activation disrupts this process, our work provides a new perspective on insulin signaling and its dysregulation in metabolic disease.