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.