Insulin‐like growth factor binding protein‐3 (IGFBP‐3): Novel ligands mediate unexpected functions

In addition to its important role in the regulation of somatic growth by acting as the major circulating transport protein for the insulin‐like growth factors (IGFs), IGF binding protein‐3 (IGFBP‐3) has a variety of intracellular ligands that point to its function within major signaling pathways. The discovery of its interaction with the retinoid X receptor has led to the elucidation of roles in regulating the function of several nuclear hormone receptors including retinoic acid receptor‐α, Nur77 and vitamin D receptor. Its interaction with the nuclear hormone receptor peroxisome proliferator‐activated receptor‐γ is believed to be involved in regulating adipocyte differentiation, which is also modulated by IGFBP‐3 through an interaction with TGFβ/Smad signaling. IGFBP‐3 can induce apoptosis alone or in conjunction with other agents, and in different systems can activate caspases −8 and −9. At least two unrelated proteins (LRP1 and TMEM219) have been designated as receptors for IGFBP‐3, the latter with a demonstrated role in inducing caspase‐8‐dependent apoptosis. In contrast, IGFBP‐3 also has demonstrated roles in survival‐related functions, including the repair of DNA double‐strand breaks through interaction with the epidermal growth factor receptor and DNA‐dependent protein kinase, and the induction of autophagy through interaction with GRP78. The ability of IGFBP‐3 to modulate the balance between pro‐apoptotic and pro‐survival sphingolipids by regulating sphingosine kinase 1 and sphingomyelinases may be integral to its role at the crossroads between cell death and survival in response to a variety of stimuli. The pleiotropic nature of IGFBP‐3 activity supports the idea that IGFBP‐3 itself, or pathways with which it interacts, should be investigated as targets of therapy for a variety of diseases.