Late effects of disturbed IGF signaling in congenital diseases: Intrauterine and postnatal growth retardation

S. Cianfarani, C. Geremia, A. Puglianiello, A. Maiorana, D. Germani

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

The biologic effects of insulin-like growth factor-1 (IGF-1) are mediated by specific cell surface receptors. IGF-1 binding to the extracellular α-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 β-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.

Original languageEnglish
Title of host publicationEndocrine Development
Pages16-27
Number of pages12
Volume11
DOIs
Publication statusPublished - 2007

Publication series

NameEndocrine Development
Volume11
ISSN (Print)14217082
ISSN (Electronic)16622979

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Pediatrics, Perinatology, and Child Health
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Medicine(all)

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