Perspectives in mammalian IGFBP-3 biology: local vs. systemic action

Insulin-like growth factor (IGF) binding protein (IGFBP)-3 has traditionally been defined by its role as a binding protein and its association with IGF delivery and availability. Development of non-IGF binding IGFBP-3 analogs and the use of cell lines devoid of type 1 IGF receptors (IGF-R) have led to critical advances in the field of IGFBP-3 biology. These studies show that IGFBP-3 has IGF-independent roles in inhibiting cell proliferation in cancer cell lines. Nuclear transcription factor, retinoid X receptor (RXR)-alpha, and IGFBP-3 functionally interact to reduce prostate tumor growth and prostate-specific antigen in vivo. Moreover, IGFBP-3 inhibits insulin-stimulated glucose uptake into adipocytes independent of IGF. The purpose of this review is to highlight IGFBP-3 as a novel effector molecule and not just another "binding protein" by discussing its IGF-independent actions on metabolism and cell growth. Although this review presents studies that assume the role of IGFBP-3 as either an endocrine or autocrine/paracrine molecule, these systems may not exist as distinct entities, justifying the examination of IGFBP-3 in an integrated model. Also, we provide an overview of factors that regulate IGFBP-3 availability, including its production, methylation, and ubiquitination. We conclude with the role of IGFBP-3 in whole body systems and possible future applications of IGFBP-3 in physiology.