Recent insights into the actions of IGFBP-6

Abstract

IGFBP-6 is an O-linked glycoprotein that preferentially binds IGF-II over IGF-I. It is a relatively selective inhibitor of IGF-II actions including proliferation, survival and differentiation of a wide range of cells. IGFBP-6 has recently been shown to have a number of IGF-independent actions, including promotion of apoptosis in some cells and inhibition of angiogenesis. IGFBP-6 also induces migration of tumour cells including rhabdomyosarcomas by an IGF-independent mechanism. This chemotactic effect is mediated by MAP kinases. IGFBP-6 binds to prohibitin-2 on the cell surface and the latter is required for IGFBP-6-induced migration by a mechanism that is independent of MAP kinases. IGFBP-6 may enter the nucleus and modulate cell survival and differentiation. IGFBP-6 expression is decreased in a number of cancer cells and it has been postulated to act as a tumour suppressor. IGFBP-6 expression is increased in a smaller number of cancers, which may reflect a compensatory mechanism to control IGF-II actions or IGF-independent actions. The relative balance of IGF-dependent and IGF-independent actions of IGFBP-6 in vivo together with the related question regarding the roles of IGFBP-6 binding to IGF and non-IGF ligands are keys to understanding the physiological role of this protein.

Fig. 1

Sequence alignment of IGFBP-6 from rat, mouse, human, cow, pig and zebrafish (2 gene products). Small residues are shown in red, acidic residues in blue, basic residues in magenta, and others in green. * fully conserved residue; : strongly conserved residue with similar properties; . weakly conserved residue. Alignment was performed using Clustal Omega v 1.2.1, EMBL-EBI (www.ebi.ac.uk) (Sievers, et al. 2011)

Fig. 2

Potential roles of prohibitin-2 (PHB2) in IGFBP-6-induced rhabdomyosarcoma cell migration. IGFBP-6 binds to (1) an unknown cell surface receptor, leading to MAP kinase pathway activation. (2) IGFBP-6 also binds to PHB2 on the cell surface and indirectly increases its tyrosine phosphorylation. PHB2 is essential for IGFBP-6-induced migration either by (3) acting downstream of MAP kinases, or (4) regulating migration independently of MAP kinase activation. This figure and research were originally published in J Biol Chem. Fu P, Yang Z, Bach LA. Insulin-like growth factor binding protein-6 (IGFBP-6)-induced rhabdomyosarcoma cell migration is modulated by binding to prohibitin-2. J Biol Chem. 2013; 288: 29890–900. © the American Society for Biochemistry and Molecular Biology