Dr. Rutaganira uses choanoflagellates—the closest living single-celled relatives to animals—to study the origin of animal cell communication. Dr. Rutaganira applies chemical, genetic, and cell biological tools to probe choanoflagellate cell-cell communication, with implications for understanding not only animal cell signaling, but also the origin of multicellularity in animals.
Assistant Professor, Biochemistry
Assistant Professor, Developmental Biology
Faculty Fellow, Sarafan ChEM-H
Honors & Awards
Hanna Gray Faculty Fellow, Howard Hughes Medical Institute
Investigator, CZ Biohub
Independent Studies (1)
- Graduate Research and Special Advanced Work
BIOC 399 (Spr, Sum)
- Graduate Research and Special Advanced Work
PI4KIIIβ is a therapeutic target in chromosome 1q-amplified lung adenocarcinoma.
Science translational medicine
2020; 12 (527)
Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.
View details for DOI 10.1126/scitranslmed.aax3772
View details for PubMedID 31969487
Multistep Compositional Remodeling of Supported Lipid Membranes by Interfacially Active Phosphatidylinositol Kinases
2016; 88 (10): 5042-5045
The multienzyme catalytic phosphorylation of phosphatidylinositol (PI) in a supported lipid membrane platform is demonstrated for the first time. One-step treatment with PI 4-kinase IIIβ (PI4Kβ) yielded PI 4-phosphate (PI4P), while a multistep enzymatic cascade of PI4Kβ followed by PIP 5-kinase produced PI-4,5-bisphosphate (PI(4,5)P2 or PIP2). By employing quartz crystal microbalance with dissipation monitoring, we were able to track membrane association of kinase enzymes for the first time as well as detect PI4P and PI(4,5)P2 generation based on subsequent antibody binding to the supported lipid bilayers. Pharmacologic inhibition of PI4Kβ by a small molecule inhibitor was also quantitatively assessed, yielding an EC50 value that agrees well with conventional biochemical readout. Taken together, the development of a PI-containing supported membrane platform coupled with surface-sensitive measurement techniques for kinase studies opens the door to exploring the rich biochemistry and pharmacological targeting of membrane-associated phosphoinositides.
View details for DOI 10.1021/acs.analchem.6b01293
View details for PubMedID 27118725
Design and Structural Characterization of Potent and Selective Inhibitors of Phosphatidylinositol 4 Kinase III beta
JOURNAL OF MEDICINAL CHEMISTRY
2016; 59 (5): 1830-1839
Type III phosphatidylinositol 4-kinase (PI4KIIIβ) is an essential enzyme in mediating membrane trafficking and is implicated in a variety of pathogenic processes. It is a key host factor mediating replication of RNA viruses. The design of potent and specific inhibitors of this enzyme will be essential to define its cellular roles and may lead to novel antiviral therapeutics. We previously reported the PI4K inhibitor PIK93, and this compound has defined key functions of PI4KIIIβ. However, this compound showed high cross reactivity with class I and III PI3Ks. Using structure-based drug design, we have designed novel potent and selective (>1000-fold over class I and class III PI3Ks) PI4KIIIβ inhibitors. These compounds showed antiviral activity against hepatitis C virus. The co-crystal structure of PI4KIIIβ bound to one of the most potent compounds reveals the molecular basis of specificity. This work will be vital in the design of novel PI4KIIIβ inhibitors, which may play significant roles as antiviral therapeutics.
View details for DOI 10.1021/acs.jmedchem.5b01311
View details for Web of Science ID 000372043400012