IGFBP6 (insulin-like growth factor binding protein 6)

	Structure of the C-terminal domain of human IGFBP-6 (Headey et al., 2004; Bach et al., 2013).
Description	IGFBP-6 belongs to the insulin-like growth factor binding protein family. It is expressed as a 240 amino acid proprotein, and processed to a 213-216 amino acid mature protein. It consists of 3 domains: the N- and C-terminal domains, which contain internal disulfide bonds, are joined by a linker domain. It contains 8 disulfide bonds, 5 in the N-terminal IGFBP domain and 3 in the C-terminal domain (Neumann et al., 1998; Neumann and Bach, 1999). Of these, the first 3 N-terminal disulfides are unique, whereas the remaining 2 N-terminal and 3 C-terminal disulfides are homologous with other IGFBPs. A peptide based on the N-terminal subdomain is largely unstructured (Chandrashekaran et al., 2007), whereas the IGF binding subdomain is conserved with other IGFBPs. Human IGFBP-6 is O-glycosylated on 5 Ser/Thr residues within the linker domain, which has a distinct sequence from other IGFBPs (Bach et al., 1992; Neumann et al., 1998). The C-terminal domain contains a thyroglobulin type 1 fold (Headey et al., 2004), which is also true for other IGFBPs, and a functional nuclear localization sequence (Iosef et al., 2008).
Expression	IGFBP6 is widely expressed in human tissues, with low levels of transcripts found in most tissues. Expression is highest in smooth muscle, olfactory bulb, ganglia, retina and the atrioventricular node (Wu et al., 2013). IGFBP6 is also found in many body fluids, including serum, cerebrospinal fluid, amniotic fluid, and follicular fluid (Baxter and Saunders, 1992; Bach, 1999; Kolker et al., 2012). IGFBP6 expression is regulated in a cell-specific manner by cAMP, IGFs, retinoic acid, vitamin D, glucocorticoids, p53, beta-catenin, hedgehog, TGF-beta and SEMA3B (Bach et al., 2013).
Localisation	Predominantly extracellular. Nuclear localization via a C-domain nuclear localization signal that binds importin-a has also been reported (Iosef et al., 2008).
Function	Unlike other IGFBPs, IGFBP-6 has a ~50-fold binding preference for IGF-II over IGF-I. It therefore is a relatively specific inhibitor of IGF-II actions (Bach, 1999; Bach, 2005; Bach et al., 2013). It is antiproliferative and proapoptotic in a number of cell lines in vitro (Bach, 1999; Bach, 2005; Bach et al., 2013). At least some of its actions in regulating cell fate are mediated by interaction with Ku80, a DNA-end binding protein (Iosef et al., 2010). IGFBP-6 has also been reported to have IGF-independent actions, such as promotion of cancer cell migration an IGF-independent mechanism that involves binding prohibitin-2 (Fu et al., 2007; Fu et al., 2013) and angiogenesis (Zhang et al., 2012). It has been reported to be a tumor suppressor in nasopharyngeal cancer through regulation of EGR-1 expression (Kuo et al., 2010). As well as binding IGFs with high affinity, IGFBP-6 also binds other unrelated proteins, including importin-α, prohibitin-2 and Ku80 as described above. Other proteins that bind IGFBP-6 inhibits osteoblast differentiation, which may be mediated by binding to LIM mineralization protein-1 (LMP-1) (Strohbach et al., 2008), the vitamin D receptor (Cui et al., 2011), and the thyroid hormone-α receptor (Qiu et al., 2012). Global deletion of IGFBP6 expression does not result in a major phenotype, presumable because of functional redundancy with other IGFBPs.
Homology	IGFBP-6 shares homology with IGFBPs 1-5 in its N-terminal IGF binding domain and its C-terminal domain. It shares homology in its C-domain with other proteins containing a thyroglobulin type 1 fold. IGFBP-6 is found in mammalian species including man, cow, rat and mouse, as well as trout and salmon. The IGFBP6 gene is duplicated in zebrafish, and each gene has a distinct expression pattern; however, overexpression of either gene inhibits embryonic growth and development (Wang et al., 2009).

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