title: IGF-independent effects of insulin-like growth factor binding protein-5 (Igfbp5) in vivo.
abstract: IGF activity is regulated tightly by a family of IGF binding proteins (IGFBPs). IGFBP-5 is the most conserved of these and is up-regulated significantly during differentiation of several key lineages and in some cancers. The function of IGFBP-5 in these physiological and pathological situations is unclear, however, several IGFBP-5 sequence motifs and studies in vitro suggest IGF-independent actions. Therefore, we aimed to compare the phenotypes of mice overexpressing wild-type Igfbp5 or an N-terminal mutant Igfbp5 with negligible IGF binding affinity. Both significantly inhibited growth, even at low expression levels. Even though wild-type IGFBP-5 severely disrupted the IGF axis, we found no evidence for interaction of mutant IGFBP-5 with the IGF system. Further, overexpression of wild-type IGFBP-5 rescued the lethal phenotype induced by "excess" IGF-II in type 2 receptor-null mice; mutant IGFBP-5 overexpression could not. Therefore, wild-type IGFBP-5 provides a very effective mechanism for the inhibition of IGF activity and a powerful in vivo mechanism to inhibit IGF activity in pathologies such as cancer. This study is also the first to suggest significant IGF-independent actions for IGFBP-5 during development.
authors.affiliation: Laboratory of Molecular Signalling, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Tripathi
authors.forename: Dervis A M
authors.initials: DA
authors.lastname: Salih
authors.forename: Anja C
authors.initials: AC
authors.lastname: Drozd
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Cosgrove
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Cobb
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pell