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One of the important regulators for growth and development of the human body is the endocrine system. The endocrine system is composed of glands that secrete hormones into the circulatory system, which are then distributed throughout the body, regulating the function of tissues and maintaining homeostasis. Among these hormones are the insulin-like growth factors (IGF), similar in molecular structure to insulin and playing an important role in cell growth, proliferation, differentiation (LeRoith & Roberts, 2003). A complex network of molecules, including its binding proteins, proteases and receptors, which together comprise the ‘IGF system’, modulates the biological function of the IGFs. This system comprises the following components (Figure 1): (i) Two peptide hormones, IGF-1 and 2, (ii) type 1 and type 2 IGF receptors, (iii) six IGF-binding proteins (IGFBP; numbered 1-6) and (iv) IGFBP proteases. IGF-1 and -2 are small signalling peptides (~7.5 kDa) that stimulate action by binding to specific cell surface receptors (IGF-1R) evoking subsequent response inside the cell. Six soluble IGF binding proteins, the IGFBPs, which range in size from 22-31 kDa and share overall sequence and structural homology with each other, regulate the activity of the IGFs. IGFBPs bind strongly to IGFs (KD ~ 300-700 pM) to ensure that the majority of circulating IGF in the blood stream is sequestered and at the tissue level inhibit the action of IGFs by blocking their access to the receptors. Proteolysis of the IGFBPs dissociates IGFs from the complex, enabling them to bind and activate the cell surface receptors (Figure 1). In tissues, IGFs form a binary complex with IGFBPs, whereas circulating IGFs are associated in ternary complexes containing IGFBP-3 (and IGFBP-5) and a third protein known as the acid-labile subunit (ALS). The ternary complex has a molecular mass of 150 kDa. The most abundant IGFbinding protein in the circulation is IGFBP-3 followed by IGFBP-2. In recent years, the IGF system in general and IGFBPs in particular have become the focus as clinically important targets of cancer therapeutics (Chan et al., 1998; Harrison et al., 1996; LeRoith & Roberts, 2003; Ma et al., 1999; Rosenzweig & Atreya, 2010; Wu et al., 2004; Yu et al., 1999). Different strategies have been proposed to inhibit cancer growth by blocking IGFI-R binding and function (recently reviewed by (Rosenzweig & Atreya, 2010)). In this regard, the therapeutic potential of the IGFBPs in inhibiting IGF-1/IGF-2 activity and thereby inhibiting cancer cell growth has been demonstrated. Notably, the IGFBPs do not bind insulin and thus do not interfere with insulin-insulin receptor interactions.

Insulin-Like Growth Factor System in HIV/AIDS: A Structure Based Approach to the Design of New Therapeutics