Lymphatic vessels serve as the body's essential drainage system, responsible for collecting interstitial fluid from tissues. Impaired lymphatic function, stemming from underdeveloped, damaged, or dysfunctional vessels, can lead to lymphedema, characterized by swelling, predominantly in the limbs. Conversely, an overgrowth of lymphatic vessels around tumors can accelerate cancer metastasis by providing pathways for malignant cells to disseminate. A recent investigation by Korean researchers has illuminated how Vascular Endothelial Growth Factor-C (VEGF-C) intensifies lymphangiogenic signaling.
A collaborative research effort, spearheaded by Professor Ho Min Kim from KAIST's Department of Biological Sciences and Dr. Sangkyu Lee of the Institute for Basic Science (IBS), successfully elucidated the three-dimensional structure of the VEGF-C-VEGFR-3 complex. Their findings demonstrate that VEGF-C facilitates the assembly of two VEGFR-3 receptors, and these resultant complexes subsequently aggregate into larger clusters, thereby amplifying the signaling cascade.
Upon VEGF-C binding to VEGFR-3 on the cell membrane, the receptor becomes active, triggering intracellular signals that govern the development and operation of lymphatic vessels. While VEGF-C-mediated dimerization of two VEGFR-3 receptors was previously recognized as a crucial step in receptor activation, the subsequent signal amplification remained largely uncharacterized. Employing cryogenic electron microscopy (cryo-EM), the research team visualized the VEGF-C-VEGFR-3 complex structure in exquisite detail. They observed that the VEGF-C-induced complexes, each comprising two VEGFR-3 receptors, further arranged themselves laterally into higher-order clusters along the cell membrane. This mechanism is akin to individual teams forming to tackle a task, then multiple teams consolidating to enhance their collective strength. The researchers validated that this clustering indeed magnifies signaling by manipulating the contact regions between complexes and controlling receptor aggregation using light, confirming its pivotal role in signal amplification.
This groundbreaking study uncovers a novel point for potential regulation of lymphangiogenic signaling. Future research can explore methods to stimulate signaling in cases of inadequate lymphatic vessel formation or to inhibit it when excessive lymphatic vessels promote tumor growth. However, further investigation is necessary to translate these findings into effective treatments for conditions such as lymphedema and cancer metastasis.