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

Abstract

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.

Fig. 1

Kaplan-Meier plots showing the probability of recurrence-free survival for 478 patients with basal-type breast cancers, from a total of 2,977 breast cancer patients, that express either high or low IGFBP-3 mRNA (A) or EGFR mRNA (B), as indicated, autoselecting the best cut-off value. Data calculated using the KM Plotter online survival analysis tool (Györffy, et al. 2010)

Fig. 2

Four hours after treatment with 20 μM etoposide, complexes between IGFBP-3 and DNA-PKcs increase in MDA-MB-468 breast cancer cells, predominantly within the nucleus. This increase is blocked by the EGFR kinase inhibitor gefitinib. (A) IGFBP-3-DNA-PKcs interactions are visualized by proximity ligation assay. (B) Quantitation of nuclear and extranuclear complexes. The percentage of complexes detected within nuclei by confocal microscopy (%N) is indicated. *, P < 0.05 compared to control-treated cells. Adapted from (Lin, et al. 2012).

Fig. 3

Proposed role of IGFBP-3 in regulating the balance between cell cycle arrest/cell death, and autophagy/cell survival. IGFBP-3 can promote apoptosis alone or in conjunction with ceramide and other agents, but suppresses ceramide generation by downregulating sphingomyelinases. By stimulating sphingosine kinase 1 (SphK1), IGFBP-3 can increase pro-survival sphingosine-1-phosphate (S1P), thus potentiating EGFR activation and cooperating with DNA-PKcs to permit DNA double-strand break repair by non-homologous end-joining (NHEJ). IGFBP-3 also promotes autophagy through interaction with GRP78. See text for details. By regulating both DNA damage repair and cell cycle arrest/apoptosis, IGFBP-3 has both caretaker and gatekeeper roles