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OPCML is a glycosyl phosphatidylinositol (GPI)-anchored cell adhesion-like molecule and a member of the IgLON family, denoting the immunoglobulin domain protein family that includes limbic system-associated membrane protein, neurotrimin, OPCML, and more recently neuronal growth regulator 1. The IgLONs are medium-sized proteins (~55 kDa) comprising 3 conserved extracellular I-type immunoglobulin domains that share common molecular recognition properties enabling homo- and heterodimerization between family members. GPI-anchored proteins are trafficked to the plasma membrane and usually are associated with detergent-insoluble fractions termed “lipid rafts” that mainly consist of cholesterol and sphingolipids.
OPCML, an opioid-binding protein/cell adhesion molecule, is crucial for regulation of opioid binding and associated signal transduction. It was originally isolated from the brain but recently has been shown to be expressed in other tissues such as stomach, oviduct, ovaries, and uterus. Although its role in the female reproductive system is presently unknown, the frequent downregulation of OPCML due to loss of heterozygosity or epigenetic inactivation at 11q25 in ovarian tumors triggered investigation into its role as a tumor suppressor. It was reported that tumors with ectopic expression of OPCML were significantly reduced in growth rate in mice compared with tumors lacking OPCML expression; this phenomenon has subsequently been observed in other cancer types, including colon, breast, prostate, and cervix.
The research conducted by McKie and colleagues showed that OPCML downregulates a variety of important receptor tyrosine kinases (RTK), such as Eph receptor A2 (EphA2), human epidermal growth factor receptor 2 (HER2) and fibroblast growth factor receptors (FGFR), via binding to their extracellular domain in ovarian cancer cells. Using HER2 as a paradigm, McKie et al. further showed that this protein-protein interaction led to the redistribution of HER2 within the cell membrane, thereby allowing its escape from the canonical clathrin endocytic route. Therefore, recycling of HER2 was less likely to occur. This decrease in the recycling of HER2, coupled with its subsequent polyubiquitination, resulted in the efficient downregulation of HER2 (Figure 1). The result opens up opportunities for using rOPCML to treat cancer without the need for intracellular delivery, a major hurdle for cancer treatment.
Figure 1. Schematic illustration of the mechanism by which rOPCML mediates its antitumor effect in OPCML-negative cells.
The RTK AXL has recently emerged as a promising therapeutic target in ovarian cancer where it is overexpressed and confers poor prognosis. In the recent study, as a result of clinical insights suggesting a survival modulating link between AXL and OPCML, researchers found that Gas6-mediated AXL activation is profoundly diminished by the GPI-anchored tumor suppressor OPCML. The interaction between OPCML and AXL is enhanced in the presence of Gas6, because OPCML shows a higher affinity for AXL when bound to its ligand. This binding leads to the redistribution of AXL from the soluble membrane fraction to the cholesterol-rich, detergent-insoluble membrane compartment. Meanwhile, they observed that a high OPCML/AXL ratio confers a better overall survival in patients affected by some different types of cancer, underscoring the potentiality of developing therapeutic agents based on targeting OPCML/AXL pathways. Furthermore, the findings in this study suggest that OPCML-based therapeutics would be effective in modulation of RTK networks as opposed to linear systems. The effectiveness of disrupting nodes of oncogenic signaling would depend on minimizing the bypass redundancy of RTK cross-talk, and this could represent an effective treatment strategy.