Current ideas on the biology of IGFBP-6: More than an IGF-II inhibitor?

IGFBP-6 binds IGF-II with higher affinity than IGF-I and it is a relatively specific inhibitor of IGF-II actions. More recently, IGFBP-6 has also been reported to have IGF-independent effects on cell proliferation, survival, differentiation and migration. IGFBP-6 binds to several ligands in the extracellular space, cytoplasm and nucleus. These interactions, together with activation of distinct intracellular signaling pathways, may contribute to its IGF-independent actions; for example, IGF-independent migration induced by IGFBP-6 involves interaction with prohibitin-2 and activation of MAP kinase pathways. A major challenge for the future is delineating the relative roles of the IGF-dependent and -independent actions of IGFBP-6, which may lead to the development of therapeutic approaches for diseases including cancer.