Lymphatic vessels act as the body’s “drainage system,” collecting excess fluid from tissues. When lymphatic drainage is impaired because lymphatic vessels are underdeveloped, damaged, or dysfunctional, lymphoedema can develop, causing swelling, particularly in the arms and legs.
Conversely, excessive lymphatic vessel growth around tumours can facilitate cancer metastasis by providing routes for tumour cells to spread. Korean researchers have discovered that VEGF-C brings two VEGFR-3 receptors together, and the resulting VEGF-C–VEGFR-3 complexes further cluster to amplify signalling. Targeting this clustering process may provide a new strategy for either enhancing or suppressing lymphangiogenic signalling, depending on the disease context.
KAIST announced that a joint research team led by Ho Min Kim from the Department of Biological Sciences at KAIST and Sangkyu Lee of the Institute for Basic Science (IBS) determined the three-dimensional structure of the VEGF-C–VEGFR-3 complex and identified how higher-order clustering of these complexes amplifies signalling.
When VEGF-C binds to VEGFR-3 on the cell surface, the receptor is activated and signals that regulate the formation and function of lymphatic vessels are transmitted into the cell. Until now, VEGF-C-mediated dimerisation of two VEGFR-3 receptors has been considered a key step in receptor activation. However, how the signal becomes further amplified after this step has not been fully understood.
The research team examined the structure of VEGF-C bound to VEGFR-3 using cryogenic electron microscopy (cryo-EM), which enables detailed visualisation of the three-dimensional structures of proteins. They found that VEGF-C-induced complexes containing two VEGFR-3 receptors further assembled side by side into higher-order clusters.
This revealed a new structural mode by which VEGF-C–VEGFR-3 complexes can organise laterally along the cell membrane. It is like two people first forming a team to begin a task, and then multiple teams gathering together to increase their collective strength. The researchers also tested whether this clustering actually amplifies signalling. By altering the regions where the complexes contact one another and by using light to control receptor clustering, they confirmed that the gathering of multiple complexes plays an important role in signal amplification.
The study identifies a new point at which lymphangiogenic signalling could potentially be regulated. In the future, researchers may explore ways to enhance signalling when lymphatic vessel formation is insufficient and to suppress signalling when excessive lymphatic vessels form around tumours. However, the study did not demonstrate therapeutic effects for lymphoedema or the inhibition of cancer metastasis, and further research will be required before the findings can be applied to actual treatments.
Ho Min Kim said: “This study reveals how two VEGFR-3 receptors first form a ligand-induced pair, after which multiple such complexes cluster together to further amplify the signal for lymphangiogenesis. By identifying this previously unseen ‘hidden amplification switch’ in lymphangiogenic signalling, we expect this work to provide an important foundation for developing new therapeutic strategies for related diseases such as lymphoedema and cancer metastasis.”
Ryeongeun Cho of the KAIST InnoCORE AI-CRED Innovative Drug Research Group and Jinsook Ahn of the KAIST Department of Biological Sciences participated in the study as co-first authors. Ho Min Kim and Sangkyu Lee led the research as co-corresponding authors. The findings were published in the journal Advanced Science.