IGFBP-6 five years on; not so 'forgotten'?
Insulin-like growth factor binding protein (IGFBP)-6 is unique among IGFBPs for its IGF-II binding specificity. IGFBP-6 inhibits growth of a number of IGF-II-dependent cancers, including rhabdomyosarcoma, neuroblastoma and colon cancer. Although the major action of IGFBP-6 appears to be inhibition of IGF-II actions, a number of studies suggest that it may also have IGF-independent actions. Gene array studies show regulation of IGFBP-6 in many circumstances that are consistent with antiproliferative actions. However, other studies show the opposite, so that IGFBP-6 may be acting as a counter-regulator in these situations or it may have other as yet undetermined actions. Both the N-terminal and C-terminal domains of IGFBP-6 contribute to high affinity IGF binding, and the C-terminal domain appears to confer its IGF-II specificity. The three-dimensional structure of the C-domain of IGFBP-6 contains a thyroglobulin type 1 fold, and the IGF-II binding site is located in the proximal half of this domain adjacent to the glycosaminoglycan binding site. Future studies are needed to further delineate the putative IGF-independent actions of IGFBP-6 and to build on the structural information to enhance our understanding of this IGFBP. This is particularly significant since IGFBP-6 provides an attractive basis for therapy of IGF-II-dependent tumors.
Bach
Leon A
LA
Department of Endocrinology and Diabetes, Alfred Hospital, Melbourne, Vic. 3004, Australia. leon.bach@med.monash.edu.au
D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011487:Protein Conformation
D018976:Insulin-Like Growth Factor Binding Protein 6; D007335:Insulin-Like Growth Factor II