Elucidation of cancer-related signaling and regulatory mechanisms by single-molecule imaging and super-resolution microscopy

Mutations in cell growth factor receptors and their downstream signaling molecules result in a state of constant cell proliferation signaling, causing cells to become cancerous, and cells continue to grow even when they are not needed. Thus, most anticancer drugs are inhibitors of cell growth factor receptors. More recently, specific inhibitors of downstream signaling molecule mutants have also begun to be used as anticancer agents. Cell growth factors associated with cell canceration are receptor-type tyrosine kinases, such as EGF receptor (EGFR), HER2, MET, and FGF receptor (FGFR), which dimerize and induce downstream signaling by autophosphorylation of tyrosine groups in their intracellular domains. When a homeostatic mutation is introduced into K-RAS, a downstream signaling molecule, K-RAS continues to signal cell proliferation.

 In our laboratory, we have elucidated the above signaling mechanisms related to cell oncogenesis by high-speed single molecule and super-resolution microscopy in living cells. For example, we found that the interaction between the extracellular domain of the growth factor receptors and the surrounding glycolipids induces a conformational change of the extracellular domain and suppresses the activation of the receptor. Furthermore, we have found that K-RAS, a signal molecule in the inner leaflet of the plasma membrane downstream of the receptor, is activated within lipid domains, causing downstream signal transduction. In the future, we hope to elucidate these signaling and regulatory mechanisms from the first principles by single-molecule and super-resolution microscopy and use this information for clinical and drug discovery purposes.