The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific
cell surface receptors. IGF-1 binding to the extracellular -subunits activates the tyrosine
kinase intrinsic to the cytoplasmic portion of the IGF-1 receptor, leading to autophosphorylation
of specific tyrosine residues in the receptor -subunit. One early molecular event that
links the receptor kinase to the biologic actions of IGF-1 is tyrosine phosphorylation of the
insulin receptor substrate family (IRS-1 to -4). IRS acts as a multisite ‘docking’ protein by
binding to downstream signal-transducing molecules. Phosphorylation of multiple tyrosine
residues results in the association of IRS-1 with the Src homology 2 (SH2) domains of other
cytoplasmic signaling proteins, including phosphatidylinositol 3 kinase, Syp, Grb2 and
Nck. By binding to Grb2, IRS proteins couple the IGF-1 receptor to the Ras/mitogenactivated
protein kinase pathway. This pathway regulates cell growth, differentiation and
proliferation. Severe pre- and postnatal growth retardation may arise from abnormalities of
IGF-1 signaling such as IGF-1-binding alterations and IGF-1 receptor mutations. Knockout
studies have shown severe growth impairment in mice lacking IRS family components or
Akt. Finally, in human placentas from pregnancies complicated by intrauterine growth
retardation, multiple alterations of IGF-1-signaling molecules have recently been described
