Late effects of disturbed IGF signaling in congenital diseases.
The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular alpha-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 beta-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.
Cianfarani
Stefano
S
Rina Balducci Center of Pediatric Endocrinology, Department of Public Health and Cell Biology, Tor Vergata University, Rome, Italy.
Geremia
Caterina
C
Puglianiello
Antonella
A
Maiorana
Arianna
A
Germani
Daniela
D
D004700:Endocrine System Diseases / Q000151:congenital* / Q000235:genetics*; D005260:Female; D005317:Fetal Growth Retardation / Q000209:etiology / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D010922:Placenta Diseases / Q000235:genetics; D011247:Pregnancy; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000235:genetics* / Q000502:physiology; D013997:Time Factors
D013002:Somatomedins; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin