Figure 2. Insulin/IGF-1 and -2 signaling and imprinted genes. In mammals, there are three insulin factors (insulin, IGF-1, and IGF-2) that bind to two tyrosine kinase receptors, insulin receptor (InsR), and IGF-1 receptor (IGF-1R). Igf2R is a non-signaling mannose-type sink receptor for IGF-2. Depending on cell type, activation of InsR and IGF-1R lead to metabolic and proliferative responses. RasGrf1 is a small GTP exchange factor (GEF) and is involved in signaling from InsR and IGF-1R. VSELs, due to changes in the epigenetic state of parentally imprinted genes, show a decrease in Igf-2 and RasGrf1 expression (green) and Igf2R overexpression (red). These epigenetic changes in genes regulating insulin/Igf signaling keep VSELs quiescent in adult tissues. We hypothesize that chronic exposure to Ins/Igf accelerates premature depletion of VSELs, while RasGrf1 deficiency has the opposite effect.