IGF-II (Insulin-like growth factor II; also multiplication-stimulating polypeptide/MSP and somatomedin-A) is a secreted 8 kDa polypeptide that belongs to the insulin family of peptide growth factors. It is part of a complex system of growth and metabolic-regulating proteins that is particularly important during development. It has been associated with nervous system proliferation and differentiation, myelination, adrenal cortical proliferation, and skeletal growth and differentiation . In human, IGF-II is primarily synthesized by the liver, and circulates at high levels in both fetus and adult. In rodent, however, IGF-II levels drop after the perinatal period, an effect attributed to the lack of a key gene promoter . This may indicate that postnatally, IGF-II has either a limited, or local effect only in rodent. For example, evidence suggests IGF-II may be the intermediary for SHH induction of VEGF attendant with local neovascularization . Rodent cells known to express IGF-II include astrocytes , hepatocytes , osteoblasts , embryonic striated muscle cells plus Kupffer cells and Ito cells . Mouse IGF-II is synthesized as a 180 amino acid (aa) preproprecursor). It contains a 24 aa signal sequence, a 67 aa mature region, and an 89 aa C-terminal prodomain that is alternatively referred to as the E-peptide. Mature IGF-II is 91% and 97% aa identical to human and rat IGF-II, respectively. Proper processing of IGF-II requires the chaperone activity of GRP94 . This generates an 8 kDa mature form, an 18 kDa, 156 aa proform, and a potential 11 kDa, 88 aa “Big” form (aa 25-112). This 11 kDa ”Big” form would be equivalent to human 15-16 kDa IGF-II, with the 5 kDa difference attributable to the presence of O-linked glycosylation . There is an additional 34 aa proteolytic fragment that is termed preptin and contains aa 93-126 of the preproprecursor. This is distinct from IGF-II, is secreted by pancreatic b cells, and facilitates insulin secretion. IGF-II has multiple binding partners. It binds to IGF-IR, the Insulin receptor (IR)-type A and IGF-IR:IR-A hybrids, the type 2 IGF receptor (IGF-2R), and IGF binding proteins 1-6 . The first three receptors initiate downstream signaling events, the IGF-2R sequesters local IGF-II, and the six IGFBPs regulate IGF-II activity in various tissues.