IGF-I and -II signal through the IGF-I Receptor, which is homologous to the Insulin Receptor. The high-affinity IGF-II Receptor does not play a direct role in signaling, but regulates the concentration of free IGF-II. The IGFs are involved in skeletal growth, and are essential for prevention of apoptosis. Serum levels of free IGFs are kept low by the action of IGF binding proteins (IGFBPs), which sequester the IGFs. Overexpression of IGFBPs may induce apoptosis, presumably by reduction of free IGF; IGFBP levels are also altered in some cancers. The IGF-I Receptor is not as mitogenic as some other growth factor receptors, but its ability to activate the PI3 Kinase pathway, through the Insulin Receptor Substrate (IRS) proteins, is critical for mediating cell survival.