Abstract
Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), one of the six members of the IGFBP family, is a key protein in the IGF pathway. IGFBP-3 can function in an IGF-dependent as well as in an IGF-independent manner. The IGF-dependent roles of IGFBP-3 include its endocrine role in the delivery of IGFs from the site of synthesis to the target cells that possess IGF receptors and the activation of associated downstream signaling. IGF-independent role of IGFBP-3 include its interactions with the proteins of the extracellular matrix and the proteins of the plasma membrane, its translocation through the plasma membrane into the cytoplasm and into the nucleus. The C-terminal domain of IGFBP-3 has the ability to undergo cell penetration therefore, generating a short 8-22-mer C-terminal domain peptides that can be conjugated to drugs or genes for effective intracellular delivery. This has opened doors for biotechnological applications of the molecule in molecular medicine. The aim of this this review is to summarize the complex roles of IGFBP-3 within the cell, including its mechanisms of cellular uptake and its translocation into the nucleus, various molecules with which it is capable of interacting, and its ability to regulate IGF-independent cell growth, survival and apoptosis. This would pave way into understanding the modus operandi of IGFBP-3 in regulating IGF-independent processes and its pleiotropic ability to bind with potential partners thus regulating several cellular functions implicated in metabolic diseases, including cancer.
Highlights
Insulin-like growth factors (IGF), known as somatomedin C or non-suppressible insulin-like activity, are mitogenic peptides that play an important role in regulating cellular proliferation, growth, differentiation, survival, migration and development
Some proteins like Mac25 known as IGF binding proteins (IGFBPs)-7 and proteins that are members of connective tissue growth factor cysteine rich protein (CCN) family possess some structural homology with IGFBPs, they lack the affinity for IGFs
This study identified the phosphorylation of IGFBP-3 at the plasma membrane and that both processes could be inhibited by IGF-1
Summary
Insulin-like growth factors (IGF), known as somatomedin C or non-suppressible insulin-like activity, are mitogenic peptides that play an important role in regulating cellular proliferation, growth, differentiation, survival, migration and development. Other researchers demonstrated that the cellular uptake of IGFBP-3 and unrelated proteins tagged with GAG binding domain of IGFBP-3 could be mapped to a 14-mer peptide containing residues 223–236 (Singh et al, 2004). Classical Cellular Uptake of IGFBP-3 Through Clathrin-Coated Pits Insulin-like growth factor binding protein-3 can interact with transferrin (Weinzimer et al, 2001) and it has been proposed that transferrin in turn can interact with its receptor, enabling the internalization of IGFBP-3 through receptormediated endocytosis along with transferrin (Lee et al, 2004). Insulin-like growth factor binding protein-3 has been demonstrated to interact with a cell surface protein, TGF-β receptor V (TGF-βV) known as IGFBP-3 receptor (IGFBP3R), which is a Ser/Thr kinase (Leal et al, 1997; Baxter, 2001). The association of transglutaminase, which possess intrinsic tyrosine kinase activity has been demonstrated
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