IGF2R

IGF2R Full Name

insulin-like growth factor 2 receptor

IGF2R Introduction

IGF2R, also referred to as the insulin-like growth factor 2 receptor or cation-independent mannose-6-phosphate receptor (CI-MPR), is an unusually multifunctional cell surface and intracellular trafficking protein that defies simple classification as a hormone receptor. Unlike kinases or classic growth factor receptors, IGF2R is a large single-pass transmembrane glycoprotein with a substantial extracellular/lumenal region composed of multiple repeating domains that can bind insulin-like growth factor 2 (IGF-2) and mannose-6-phosphate (M6P)-tagged proteins at distinct sites on the same molecule. This dual affinity enables it to serve as both a regulator of external growth factor availability and an intracellular sorting receptor that shuttles lysosomal enzymes from the Golgi apparatus to endosomes and lysosomes, with ligand release occurring in low-pH compartments and the receptor recycled for repeated rounds of cargo transport.

Figure 1.IGF2R activation and signaling.(Sources: Castro JJ, et al.; 2023)

At the molecular level, IGF2R does not signal via intrinsic kinase activity; instead, it attenuates IGF-2-driven proliferative signaling by binding and internalizing IGF-2 for degradation, effectively acting as a "sink" that limits the hormone's interaction with IGF1R and related receptors. This capacity to curb IGF-2 excess places IGF2R in a balancing role for cell growth, differentiation and metabolism, while its mannose-6-phosphate binding domains orchestrate the intracellular trafficking of acid hydrolases and other M6P-tagged proteins, a process essential for lysosomal biogenesis and protein turnover. IGF2R also participates in processing latent growth inhibitors like transforming growth factor-β1 and may influence immune cell coactivation and endocytic pathways, reflecting its integration into broader cellular regulatory networks.

Disruption of IGF2R expression or function has been linked to pathological states across multiple systems. In cancer biology, reduced IGF2R activity or loss of heterozygosity has been associated with enhanced IGF-2 signaling and tumor progression in hepatocellular carcinoma and other malignancies, consistent with its proposed role as a tumor suppressor that restrains unchecked growth signals. Altered trafficking of lysosomal enzymes due to IGF2R mutations contributes to storage disorders and may have implications for other diseases, while research also implicates IGF2R in cardiovascular remodeling and muscle homeostasis, where its modulation of growth factor dynamics can affect cellular survival and stress responses. These varied roles explain why IGF2R is a valuable research target; scientists commonly use IGF2R antibodies, recombinant proteins, trafficking assays, and ligand-binding screening tools to dissect its contributions to both normal physiology and disease mechanisms in translational and therapeutic contexts.

Alternate Names for IGF2R

IGF2R; insulin-like growth factor 2 receptor; MPR1; MPRI; CD222; CIMPR; M6P-R; cation-independent mannose-6-phosphate receptor; M6PR; CI-MPR

• 1. Castro JJ, et al.; DHA Supplementation during Pregnancy in Women with Obesity Normalizes IGF2R Levels in the Placenta of Male Newborns. Int J Endocrinol. 2023, 2023:1515033.