Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment

Abstract

Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects. Conclusion: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer. (HEPATOLOGY 2014;59:974-985)

Crystal Structure of Human Leukocyte Cell-derived Chemotaxin 2 (LECT2) Reveals a Mechanistic Basis of Functional Evolution in a Mammalian Protein with an M23 Metalloendopeptidase Fold

“…Most recently, it was reported that LECT2 can bind to the receptor tyrosine kinase human c-mesenchymal epithelial transition factor (c-Met). This binding is antagonistic to the c-Met receptor activation, and LECT2 acts as a tumor suppressor in HCC (32). This finding suggests an alternative function in which LECT2 is involved in protein-protein interaction.…”

“…The interaction between LECT2 and c-Met ECD has been demonstrated by coimmunoprecipitation experiments. The LECT2 binding caused an antagonistic effect on the c-Met receptor activation (32). In our study, the kinetic measurements of the interaction between these proteins were performed for the first time using surface plasmon resonance methods.…”

Leukocyte Cell–Derived Chemotaxin 2–Associated Amyloidosis

“…A study on Ayu (plecoglossus altivelis) showed that LECT2 interacts with a C-type lectin receptor (32). Chen et al (33) recently showed that the inhibitory function of LECT2 on hepatocellular carcinoma is mediated by binding and inactivation of MET receptor, leading to blockage of vascular invasion and metastasis of hepatocellular carcinoma. Other studies showed that LECT2 negatively regulates the homeostasis of NKT cells in the liver (34,35).…”

“…LECT2 protein was initially purified from a culture fluid of phytohemagglutinin-activated human T cell leukemia SKW-3 cells as a potential chemotactic factor for human neutrophils (24). Subsequent studies indicated that it is a multifactorial cytokine involved in chemotaxis, cell proliferation, immunomodulation, damage/repair process, tumor suppression, and glucose metabolism (33,36,(41)(42)(43)(44).…”

Ectopic Fat Accumulation in the Liver and Glucose Homeostasis

“…LECT2 enhances macrophage function via the CD209a/DC-SIGN receptor and improves immunity in bacterial sepsis (53). More recently, it has been reported that LECT2 suppresses hepatocellular carcinoma by direct binding and inactivating hepatocyte growth factor (HGF) receptor MET (54). However, the role of LECT2 in the development of obesity and insulin resistance was unknown.…”