Insulin-like growth factor binding protein-3 (IGFBP-3) is one of six members of the insulinlike growth factor (IGF) binding protein superfamily which function to modulate the biological activity of IGF [1]. Human IGFBP-3 is the major binding protein of IGF where it exists in circulation as a ternary complex with the acid-labile subunit (ALS) [2]. Like other IGFBP members, human IGFBP-3 includes a cysteine-rich C-terminal domain, a highly variable central linker domain, and another N-terminal cysteine-rich domain [2, 3]. Human IGFBP-3 cDNA encodes a 291 amino acid (aa) precursor protein with a 27 aa signal peptide that is processed to generate the 264 aa mature protein. Mature human IGFBP-3 shares 82% aa sequence identity with both mouse and rat IGFBP-3. Post-translational glycosylation and phosphorylation of IGFBP-3 modifies the affinities of the binding protein. Proteolysis of IGFBP-3 by tissue plasminogen activator (tPA), a disintegrin and metaloproteases (ADAMs), and prostate specific antigen (PSA) contributes to IGFBP-3 degradation or a reduction in its affinity for IGF [4-6]. The majority of soluble IGFBP-3 found in circulation is secreted from hepatic non-parenchymal cells. IGFBP-3 expression can be modulated by p53 as well as by various cytokines and growth factors [7, 8]. In addition to its role in stabilizing and transporting circulating IGF, IGFBP-3 has been shown to potentiate EGF-EGFR-mediated cell growth through the activation of sphingosine kinase1 (SPHK1) and sphingosin-1-phosphate (S1P) [9, 10]. IGFBP-3 has also been shown to modulate adipogenesis [11]. Binding of IGFBP-3 to non-IGF-related ligands has been shown to regulate TGF-beta signaling, DNA damage, apoptosis, autophagy, and gene transcription [12].
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