The insulin-like growth factor (IGF) family of ligands and receptors are members of a highly conserved growing family of insulin-related peptides and receptors that are ubiquitously expressed. The IGF family (IGF-I, IGF-II) is distinct from insulin in the existence of a large family of high-affinity binding proteins (IGFBPs). The IGFs play important roles in numerous physiological processes. These processes range from normal growth and development during the early stages of embryogenesis to the regulation of specific functions for various tissues and organs in later stages of development. The IGFs are essential for an array of diverse processes, from progression of the cell cycle, which triggers cellular proliferation, to regulation of programmed cell death (apoptosis). These growth factors also induce cellular differentiation and stimulate certain enzymatic functions in specialized tissues. In the reproductive system, IGFs augment steroidogenesis and stimulate proliferation and differentiation of bone cells, muscle cells, and cells derived from the hematopoietic and lymphoid systems, to mention just a few examples. The total concentrations of IGF-I in the circulation are closely correlated with longitudinal growth. This and other evidence suggests that during both normal and pathophysiological situations, such as dwarfism and acromegaly, circulating IGF-I regulates body growth. In addition, locally produced IGF-I mediates critical autocrine/paracrine effects on tissues. Whatever the source of the IGFs, their biological actions are predominantly mediated by the IGF-I receptor (type 1) receptor (1). While the closely related insulin receptor is capable of binding the IGFs, this interaction is of lower affinity than of insulin for its own receptor. However, under certain circumstances, the insulin receptor may also mediate some of the biological actions of the IGFs. On the other hand, the IGF-II/mannose-6-phosphate (type 2) receptor does not appear to regulate any significant signaling cascades. Like the insulin receptor, the insulin-like growth factor I receptor (IGF-IR), is a member of the receptor tyrosine kinase family of growth factor receptors. The IGF-IR is expressed at the cell surface as a tetramer, comprised of two α and two ß subunits. The α subunits are primarily localized extracellularly and mediate ligand binding, whereas the two ß subunits are primarily intracellular and possess intrinsic tyrosine kinase activity. The IGF-IR binds IGF-I and IGF-II with high affinity, and insulin at a considerably lower affinity. Ligand binding to the extracellular receptor triggers autophosphorylation of the ß subunits and stimulates the tyrosine kinase activity. This sequence of events involves a conformational change in the catalytic loop domain of the tyrosine kinase region, binding of ATP to residue lys1003, and phosphorylation of residues tyr1131, tyr1135, and tyr1136. Each ß subunit then transphosphorylates the other, leading to phosphorylation of a number of other tyrosines including, but not limited to, tyr950 in the juxtamembrane region, tyr1250, tyr1251 and tyr1316 in the carboxyl-terminal domain of the ß subunit. Substitution of phenylalanine for tyrosine in each of these residues has resulted in a loss of function (2–7). Tyrosine phosphorylation of the IGF-I receptor has two distinct, but related, outcomes. Firstly, the tyrosine kinase activity of receptor is enhanced, and secondly, the phosphorylated tyrosine residues provide docking sites for various proteins that mediate the signaling cascades emanating from the IGF-I receptor. Previous studies have indicated that the juxtamembrane region of the cytoplasmic domain of the ß-subunit binds both Shc and the various isoforms of the IRS family of …