Several molecules that are involved in wound healing interact with the insulin-like growth factor-2 receptor (IGF2R), a 300 kDa multifunctional receptor containing 15 distinct domains (
Fig. 1) that specifically binds a diverse set of intracellular and extracellular ligands with high affinity (see reviews
14,15). These domains mediate the major known functions of the receptor: transporting newly synthesized lysosomal enzymes from the trans Golgi network to lysosomes; controlling extracellular levels of specific proteins through binding, internalization, and delivery of proteins from the extracellular milieu to lysosomes for degradation; and serving as a scaffold for proteins to interact at the plasma membrane surface. During development, the most important molecule that interacts with the receptor is IGF2, which binds to domain 11 and is delivered to the lysosome for degradation.
16,17 By regulating the circulating levels of IGF2, a growth-promoting polypeptide that signals via the IGF1 and insulin receptors,
18 IGF2R has a critical role in normal development. This key function of the receptor is supported by transgenic mice studies in which the loss of IGF2R results in death at birth, with the embryos displaying an overgrowth phenotype,
19 a phenotype that can be prevented by also knocking down IGF2.
20 In addition, knockdown (KD) of IGF2R in multiple cell types in culture results in mistargeting of lysosomal enzymes to the extracellular milieu and compromised lysosomal function.
21–24 Lysosomal enzymes and other proteins, such as renin precursor and leukemia inhibitory factor, that contain mannose 6-phosphate (M6P) as part of their N-linked high mannose-type glycans, bind to the receptor through domains 3, 5, and 9 (
Fig. 1). In addition to lysosomal enzymes and IGF2, IGF2R binds to other key regulators of corneal wound healing, including the urokinase plasminogen activator receptor (uPAR),
25 plasminogen,
26,27 connective tissue growth factor (CTGF),
28 retinoic acid,
29 and heparanase,
30 through mechanisms yet to be elucidated. This receptor may serve as a scaffold for efficient activation of plasminogen by urokinase bound to uPAR through interaction of uPAR and plasminogen to domain 1 (
Fig. 1). Binding of the receptor to a number of known molecules involved in corneal wound healing suggests IGF2R also is involved in this process.