IRS-1 acts as an endocytic regulator of IGF-I receptor to facilitate sustained IGF signaling

Mammals, including humans, use signaling molecules called hormones to carry information from one cell to another. Insulin-like growth factor (or IGF for short) is a hormone that is essential throughout an animal’s lifetime. It is needed for growth and for many of the chemical processes that must occur to maintain life (which are collectively referred to as an animal’s metabolism). IGF binds to and activates a protein found on the surface of cells, which then transmits the signal inside the cells. This surface protein is known as the IGF-I receptor, and once it is activated by IGF binding, it is removed from the cell surface and then incorporated inside the cell to switch off the signal. The IGF signal in cells needs to be properly balanced to prevent disorders of growth and metabolism. How long the activated IGF-I receptor remains at the cell surface and when the IGF-I receptor starts to enter inside the cells after cells receive IGF influence the signals within the cell. Often IGF signaling must be activated for long periods, for example when cells maintain their balance between making and breaking proteins. However, it remains poorly understood how the IGF-I receptor produces a sustained signal. Yoneyama et al. have now focused on a protein called IRS-1, which was known to act downstream of the receptor. The experiments revealed that this protein determines how long activated IGF-IR remains at the cell surface before it enters inside cells. It achieves this by binding to a complex of proteins, known as AP2, which normally internalizes the IGF-I receptor. However, when IRS-1 binds, it inhibits AP2. This means that the receptor is no longer rapidly removed from the cell surface and can continue signaling for long periods of time. The findings of Yoneyama et al. help to explain how long-term IGF signaling is regulated. Further work that builds on these findings could help scientists to understand how uncontrolled IGF signals cause the development of diseases including cancer and metabolic disorders.