40 YEARS OF IGF1: Role of IGF-binding proteins in regulating IGF responses to changes in metabolism

Abstract

The IGF-binding protein family contains six members that share significant structural homology. Their principal function is to regulate the actions of IGF1 and IGF2. These proteins are present in plasma and extracellular fluids and regulate access of both IGF1 and II to the type I IGF receptor. Additionally, they have functions that are independent of their ability to bind IGFs. Each protein is regulated independently of IGF1 and IGF2, and this provides an important mechanism by which other hormones and physiologic variables can regulate IGF actions indirectly. Several members of the family are sensitive to changes in intermediary metabolism. Specifically the presence of obesity/insulin resistance can significantly alter the expression of these proteins. Similarly changes in nutrition or catabolism can alter their synthesis and degradation. Multiple hormones such as glucocorticoids, androgens, estrogen and insulin regulate IGFBP synthesis and bioavailability. In addition to their ability to regulate IGF access to receptors these proteins can bind to distinct cell surface proteins or proteins in extracellular matrix and several cellular functions are influenced by these interactions. IGFBPs can be transported intracellularly and interact with nuclear proteins to alter cellular physiology. In pathophysiologic states, there is significant dysregulation between the changes in IGFBP synthesis and bioavailability and changes in IGF1 and IGF2. These discordant changes can lead to marked alterations in IGF action. Although binding protein physiology and pathophysiology are complex, experimental results have provided an important avenue for understanding how IGF actions are regulated in a variety of physiologic and pathophysiologic conditions.

Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain

“…M6PR expressed in peripheral tissues (Duffy et al, 1988). The transport of IGF1 or IGF2 into brain via the BBB IGFR may be inhibited, because IGF1 and IGF1 are avidly bound, >99%, in plasma by a family of IGF binding proteins (IGFBP; Clemmons, 2018). It is likely that IGFBP complex formation with either IGF1 or IGF2 blocks BBB transport of the peptide, because an IGF2-lysosomal enzyme fusion protein does not cross the BBB following IV administration (Kan et al, 2014).…”

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

“…IGFBP5/Igfbp5a has been shown to inhibit and/or potentiate IGF actions in mammalian and zebrafish cells (Zheng et al, 1998;Ren et al, 2008;Dai et al, 2010;Liu et al, 2018). How the same protein exerts these opposing biological effects is not completely understood, but the importance of IGFBP5 proteinases has been suggested (Zheng et al, 1998;Oxvig, 2015;Clemmons, 2018;Allard and Duan, 2018). Using an optimized in situ hybridization protocol and qPCR analysis of FACS-isolated NaR cells, we found that Papp-aa is highly expressed in NaR receptor-mediated Akt-Tor activity in NaR cells is off.…”

“…IGFBPs are a family of secreted proteins that bind IGF ligands with high affinity and regulates their availability to the IGF1 receptor (Baxter, 2014;Clemmons, 2018;Allard and Duan, 2018).…”

Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults

“…Circulating IGFBP-1, which is produced mainly by the liver, is normally suppressed in postprandial state by hyperinsulinemia [78] and increased glycolysis [79]. As the levels of IGFBP-1 fluctuate throughout the day in response to feeding and fasting, it acutely regulates the availability of free IGF-1, which has insulin-sensitizing effects [80]. In adipose tissue, IGFBP-1 inhibits IGF-1 stimulated proliferation of preadipocytes [81], resulting in reduced fat mass [82].…”