Jaehyuk Lee

All Publications

• Targeting Heme Oxygenase 2 (HO2) with TiNIR, a Theragnostic Approach for Managing Metastatic Non-Small Cell Lung Cancer. Biomaterials research Mun, S. K., Sim, H. B., Lee, J. H., Kim, H., Park, D. H., Lee, Y. A., Han, J. Y., Choi, Y. J., Son, J. S., Park, J., Lim, T. H., Yee, S. T., Chang, Y. T., Lee, S., Chang, D. J., Kim, J. J. 2024; 28: 0026

  Abstract

  Despite notable advancements in cancer therapeutics, metastasis remains a primary obstacle impeding a successful prognosis. Our prior study has identified heme oxygenase 2 (HO2) as a promising therapeutic biomarker for the aggressive subsets within tumor. This study aims to systematically evaluate HO2 as a therapeutic target of cancer, with a specific emphasis on its efficacy in addressing cancer metastasis. Through targeted inhibition of HO2 by TiNIR (tumor-initiating cell probe with near infrared), we observed a marked increase in reactive oxygen species. This, in turn, orchestrated the modulation of AKT and cJUN activation, culminating in a substantial attenuation of both proliferation and migration within a metastatic cancer cell model. Furthermore, in a mouse model, clear inhibition of cancer metastasis was unequivocally demonstrated with an HO2 inhibitor administration. These findings underscore the therapeutic promise of targeting HO2 as a strategic intervention to impede cancer metastasis, enhancing the effectiveness of cancer treatments.

  View details for DOI 10.34133/bmr.0026

  View details for PubMedID 38665698

  View details for PubMedCentralID PMC11045274

• A Novel Interaction between MFN2/Marf and MARK4/PAR-1 is Implicated in Synaptic Defects and Mitochondrial Dysfunction. eNeuro Cheon, Y., Yoon, S., Lee, J., Kim, K., Kim, H., Hong, S. W., Yun, Y., Shim, J., Kim, S., Lu, B., Lee, M., Lee, S. 2023

  Abstract

  As cellular energy powerhouses, mitochondria undergo constant fission and fusion to maintain functional homeostasis. The conserved dynamin-like GTPase, MFN2/Marf, plays a role in mitochondrial fusion, mutations of which are implicated in age-related human diseases, including several neurodegenerative disorders. However, the regulation of MFN2/Marf-mediated mitochondrial fusion, as well as the pathologic mechanism of neurodegeneration, are not clearly understood. Here, we identified a novel interaction between MFN2/Marf and MARK4/PAR-1. In the Drosophila larval neuromuscular junction, muscle-specific overexpression of MFN2/Marf decreased the number of synaptic boutons, and the loss of MARK4/PAR-1 alleviated the synaptic defects of MFN2/Marf overexpression. Downregulation of MARK4/PAR-1 rescued the mitochondrial hyperfusion phenotype caused by MFN2/Marf overexpression in the Drosophila muscles as well as in the cultured cells. In addition, knockdown of MARK4/PAR-1 rescued the respiratory dysfunction of mitochondria induced by MFN2/Marf overexpression in mammalian cells. Taken together, our results indicate that the interaction between MFN2/Marf and MARK4/PAR-1 is fine-tuned to maintain synaptic integrity and mitochondrial homeostasis, and its dysregulation may be implicated in neurologic pathogenesis.Significance StatementWe identified a novel interaction between MFN2/Marf and a kinase MARK4/PAR-1 in Drosophila and mammalian cells. The MFN2/Marf and MARK4/PAR-1 interaction was critical for maintaining the synaptic structure of neuromuscular junctions in Drosophila In addition, we found that concomitant knockdown of MARK4/PAR-1 could rescue the mitochondrial hyperfusion and aberrant respiratory function caused by MFN2/Marf overexpression. Our study provides new insights into the link between mitochondrial defects and neurodegeneration, which makes a significant contribution to the understanding of neurologic pathogenesis and therapeutic development.

  View details for DOI 10.1523/ENEURO.0409-22.2023

  View details for PubMedID 37550059

• Molecular characterization of ligand selectivity of the sex peptide receptors of Drosophila melanogaster and Aedes aegypti. Insect biochemistry and molecular biology Lee, J. H., Lee, N. R., Kim, D. H., Kim, Y. J. 2020; 127: 103472

  Abstract

  Drosophila melanogaster sex peptide receptor (DrmSPR) is a G protein-coupled receptor (GPCR) with 'dual ligand selectivity' towards sex peptide (SP) and myoinhibitory peptides (MIPs), which are only remotely related to one another. SPR is conserved in almost all the sequenced lophotrochozoan and ecdysozoan genomes. SPRs from non-drosophilid taxa, such as those from the mosquitoes Aedes aegypti (AeaSPR), Anopheles gambiae (AngSPR), and the sea slug Aplysia californica (ApcSPR), are highly sensitive to MIP, but not to SP. To understand how Drosophila SPRs evolved their SP sensitivity while maintaining MIP sensitivity, we examined ligand selectivity in a series of chimeric GPCRs that combine domains from the SP-sensitive DrmSPR and the SP-insensitive AeaSPR. We found replacement of Pro 238 (P238) in DrmSPR with the corresponding residue from AeaSPR (L310) reduced its SP sensitivity 2.7 fold without altering its MIP sensitivity. The P238 residue located in the third extracellular loop (ECL3) is conserved in Drosophila SPRs and in SPR from the moth Bombyx mori (BomSPR), which is considerably more sensitive to SP than AeaSPR, AngSPR, or ApcSPR. We found, however, that rather than improving AeaSPR's sensitivity to SP, replacement of L310 in AeaSPR with Pro significantly reduces its MIP sensitivity. Thus, our identification of a single amino acid residue critical for SP sensitivity, but not for MIP sensitivity is an important step in clarifying how DrmSPR evolved the ability to detect SP.

  View details for DOI 10.1016/j.ibmb.2020.103472

  View details for PubMedID 32971207

• Homology modeling and molecular docking studies of Drosophila and Aedes sex peptide receptors. Journal of molecular graphics & modelling Kim, J. H., Kim, S. K., Lee, J. H., Kim, Y. J., Goddard, W. A., Kim, Y. C. 2016; 66: 115-22

  Abstract

  The Drosophila melanogaster sex peptide receptor (DrmSPR), which is a G protein-coupled receptor (GPCR), is known as the specific receptor for sex peptide (SP). It is responsible for the reproductive behavior in the Drosophila model system; in particular, it is involved in the post-mating responses such as the increase in egg-laying ability and decrease in receptivity in females. In a previous study, we discovered a small molecule agonist of DrmSPR for the first time, which could not, however, activate Aedes aegypti SPR (AedesSPR). To investigate the binding mechanism of the small molecule agonist of DrmSPR, the ensemble structures of low-lying packing structures of DrmSPR and AedesSPR were assembled using the GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) method. The generated homology models exhibited the typical pattern of inter-helical interactions of the class A GPCRs. The docking experiments of the small molecule agonist suggest that Tyr(5.35) and Phe(2.67) residues may be involved in a hydrophobic interaction and that Ser(3.25) forms a hydrogen bond with the agonist. Additionally, we found that the docking results were consistent with the experimental data of the reference compounds with variable agonistic activities. Moreover, a potential distinction of the putative binding sites in two GPCR models of DrmSPR and AedesSPR, which was determined in this study, can explain the selective action of the agonist for DrmSPR but not for AedesSPR.

  View details for DOI 10.1016/j.jmgm.2016.03.014

  View details for PubMedID 27060892

• Discovery and structure-activity relationships of pyrazolodiazepine derivatives as the first small molecule agonists of the Drosophila sex peptide receptor. Bioorganic & medicinal chemistry Kim, J. H., Jeong, P. H., Lee, J. Y., Lee, J. H., Kim, Y. J., Kim, Y. C. 2015; 23 (8): 1808-16

  Abstract

  In behavioral research, the sex peptide receptor in Drosophila melanogaster (DrmSPR) is the most interesting G protein-coupled receptor (GPCR) and is involved in post-mating responses such as increased egg-laying and decreased receptivity of the female; during these responses, the receptors are activated by a specific natural peptide agonist (sex peptide, SP). To discover small molecule agonists for DrmSPR, a compound library based on a pyrazolodiazepine scaffold, which was previously reported as a potential privileged structure, was screened. Structure-activity relationship (SAR) studies of the hit compounds, which exhibited weak agonistic effects (69-72% activation at 100μM), were explored through the synthesis of various analogs with substituents at the R1, R2, R3 and R4 positions of the pyrazolodiazepine skeleton. As a result, compounds 21 and 31 of the 6-benzyl pyrazolodiazepine derivative series were found to be small molecule agonists for DrmSPR with EC50 values of 3-4μM.

  View details for DOI 10.1016/j.bmc.2015.02.035

  View details for PubMedID 25797164

• Identification of a novel insect neuropeptide, CNMa and its receptor. FEBS letters Jung, S. H., Lee, J. H., Chae, H. S., Seong, J. Y., Park, Y., Park, Z. Y., Kim, Y. J. 2014; 588 (12): 2037-41

  Abstract

  To identify ligands for orphan GPCRs, we searched novel neuropeptide genes in the Drosophila melanogaster genome. Here, we describe CNMa, a novel cyclic neuropeptide that is a highly potent and selective agonist for the orphan GPCR, CG33696 (CNMaR). Phylogenetic analysis revealed that arthropod species have two paralogous CNMaRs, but many taxa retain only one. Drosophila CNMa potently activates CNMaR-2 from Apis mellifera, suggesting both receptors are functional. Although CNMa is conserved in most arthropods, Lepidoptera lack the CNMa gene. However, they retain the CNMaR gene. Bombyx CNMaR showed low sensitivity to Drosophila CNMa, hinting toward the existence of additional CNMaR ligand(s).

  View details for DOI 10.1016/j.febslet.2014.04.028

  View details for PubMedID 24796791