Chemotaxis and signal transduction
Cells respond to environments and hormones with extreme accuracy and control their behaviors and metabolism in the human body. The Iijima laboratory aims to understand how cells sense extracellular chemicals through GPCRs and move toward high concentrations of chemoattractants. We also study how cells recognize insulin and regulate glucose homeostasis through tyrosine receptor kinases. We focus on intracellular signaling transduction mechanisms controlled by PI3-kinase, PTEN, mTORC2 and AKT. We use protein biochemistry, live-cell imaging, and mouse models to discover fundamental biology and translate this into the development of therapeutic interventions for human diseases, such as cancer and diabetes.
Cell Reports (2020)
GPCR-mediated chemotactic stimulation induces hetero-oligomerization of phosphorylated GDP-bound Rho GTPase and GTP-bound Ras GTPase in directed cell migration in the social amoebae Dictyostelium discoideum. The Rho-Ras hetero-oligomers directly activate mTORC2 toward AKT. In contrast to GDP-Rho, GTP-Rho antagonizes mTORC2-AKT signaling by inhibiting the oligomerization of GDP-Rho with GTP-Ras in the back of migrating cells. Therefore, hetero-oligomerization of Rho and Ras provides a critical regulatory step that controls mTORC2-AKT signaling.
PTEN is one of the most highly mutated tumor suppressor genes. PTEN is located in the nucleus in addition to the plasma membrane. The nuclear localization of PTEN is regulated by ubiquitination of lysine 13. Nuclear PTEN suppresses DNA damage in the liver in vivo. Nuclear PTEN loss causes tumorigenesis in a mouse model for hepatocellular carcinoma.
Mitochondrial dynamics and quality control
Mitochondria are highly dynamic: they grow, divide, and fuse in highly regulated manners. Mitochondrial division and fusion play essential roles in mitochondrial quality control to maintain this essential organelle’s health. Damaged mitochondria can be separated from healthy mitochondria by division. Fusion allows mitochondria to mix and exchange their contents. The goal of the Sesaki laboratory is to decipher the mechanisms of mitochondrial dynamics and quality control, focusing on dynamin-related GTPases, such as Drp1, Opa1, and mitofusin, as well as Parkinson’s disease proteins, Parkin and PINK1. Similar to the Iijima laboratory, our approaches extend from biochemisty using purified mitochondria, proteins, and synthetic lipids to cell biology and physiology tusing super-resolution microscopy, electron microscopy, and genetically engineered mouse models.
Mol Cell (2020)
The mitochondria division GTPase Drp1 is associated with the ER and tubulates it independently of GTP hydrolysis. ER tubules formed by Drp1 promote mitochondrial division. Therefore, Drp1 functions as a two-in-one protein during mitochondrial division, with ER tubulation and mechano-GTPase activities.
EMBO J (2020)
The balance between membrane fusion and fission controls mitochondrial connectivity and function. Here, short pulses of membrane depolarization are found to drive an Oma1‐dependent stress response termed ‘mitochondrial safeguard’ that protects mitochondrial function upon increased mitochondrial connectivity.