How many insulin-like growth factor binding proteins?

Mac25, connective tissue growth factor, the nov-oncogene and cyr61 have been proposed as insulin-like growth factor binding proteins (IGFBPs) although they bind the ligand with very low affinity. Sequence similarity between the candidate proteins and the recognised IGFBPs is restricted to a single cysteine-rich N-terminal domain. The cysteine-rich domain (CRD) can be found in other vertebrate and invertebrate proteins that are associated with the extracellular matrix but otherwise have vastly different functions. Characteristically, the proteins with the CRD have a modular architecture suggesting that exon shuffling has played a significant role in their evolution. Although the proposed candidate proteins may not be IGFBPs, linkage relationships of the latter suggest that two other IGFBPs may indeed exist.