Joseph Falke

Joseph Falke awarded 5-year MIRA / R35 NIH grant to continue research on a membrane-based signaling circuit

Anonymous — Sat, 01 Jan 2022 07:00:00 +0000

Joseph Falke awarded 5-year MIRA / R35 NIH grant to continue research on a membrane-based signaling circuit Anonymous (not verified) Sat, 01/01/2022 - 00:00

The NIH recently awarded Dr. Joseph Falke with a 5-year MIRA / R35 grant to continue their research on a membrane-based signaling circuit central to leukocyte chemotaxis and many human cancers. The grant ($2.0M total costs) begins January 1, 2022, and the lab looks forward to recruiting new members!

Abstract Text

SUMMARY At the leading edge of a polarized macrophage, a membrane-based chemotaxis pathway directs cell mi- gration up attractant gradients to sites of infection, inflammation, or tissue damage. Upon arrival, a phagocyto- sis pathway controls the formation and internalization of a phagosome in which the pathogens or damaged tis- sue are engulfed and destroyed. Both the chemotaxis and phagocytosis pathways are regulated by PI3K lipid kinases that serve as regulatory hubs by integrating Ca2+, receptor, G protein, and other input signals while phosphorylating substrate lipids to produce output lipid signals. The potent lipid signals, in turn, activate multi- ple downstream protein kinases. In chemotaxis, the lipid signal controls actin and membrane remodeling to drive the leading edge up the attractant gradient. In phagocytosis, the lipid signal controls processing of the phagosome including the production of reactive oxygen species (ROS) to inactivate pathogens. Closely related PI3K pathways regulate other cell processes, notably including cell growth. When dysregulated, PI3K path- ways trigger or exacerbate a wide array of human diseases ranging from cancer and developmental disorders to defects in innate immunity, inflammation or autoimmunity. The two classes of PI3K lipid kinases targeted by this research program are Class 1 PI3-Kinases (PI3K1) that generate the signaling lipid PIP3 at the leading edge membrane of polarized macrophages, and Class 3 PI3-Kinases (PI3K3, specifically PI3K3 Complex II) that produce PI3P on the surface of the phagosome. The proposed research seeks to understand the regulation of both pathways by addressing fundamental, broad questions including: (i) How do PI3K1 and PI3K3 regulatory hubs integrate multiple inputs from Ca2+ channels, receptors, G proteins and other effectors, and do these inputs combine in additive, synergistic, or opposing fashions? (ii) How do the resulting PIP3 and PI3P output lipids activate downstream protein kinases, including some of the most important master kinases in the cell? (iii) How do drugs, potential therapeutics, and disease- linked mutations inhibit or superactivate key components and reaction steps to generate pathway perturbation or dysregulation? To answer these and other questions, the PI's laboratory has developed a unique, two-pronged approach combining innovative, in vitro single molecule methods with live cell imaging studies. The in vitro studies utilize single molecule TIRF to elucidate signaling mechanisms in a subsection of the pathway, or signaling module, that is reconstituted on a supported lipid bilayer under near physiological conditions. The live cell studies em- ploy fluorescent sensors and cell imaging to test key predictions of the in vitro mechanistic model for relevance in the cellular context. The PI has a strong track record and continues to play leadership roles in his research field, as well as the university and scientific communities. Overall, this research program is well positioned to continue generating fundamental advances with significant impacts on signaling biology and medicine.

Public Health Relevance Statement

NARRATIVE This research program focuses on lipid signaling pathways controlled by ubiquitous PI3K lipid kinase enzymes. PI3K lipid signaling pathways play central roles in normal macrophage function during innate immunity and, when dysregulated, trigger an array of human diseases. Research is pursuing the molecular mechanisms of regulation in the normal pathway, as well as the mechanisms of dysregulation triggered by disease-linked mu- tations, and the mechanisms by which drugs and potential therapeutics drive pathway activation or inhibition.

For more information, see the NIH RePORT for this grant

Off

Traditional

White

Falke lab article selected by Biophysical Journal editors as "New and Notable"

Anonymous — Tue, 21 Dec 2021 07:00:00 +0000

Falke lab article selected by Biophysical Journal editors as "New and Notable" Anonymous (not verified) Tue, 12/21/2021 - 00:00

The Falke lab's recent publication "Single Molecule Studies Reveal Regulatory Interactions between Master Kinases PDK1, AKT1 and PKC" was selected by the Biophysical Journal editors as "New and Notable".

Moshe T. Gordon, Brian P. Ziemba, and Joseph J. Falke (2021) Single Molecule Studies Reveal Regulatory Interactions between Master Kinases PDK1, AKT1 and PKC. Biophys J. 2021 Dec 21;120(24):5657-5673. PMID: 34673053. DOI: https://doi.org/10.1016/j.bpj.2021.10.015.

New & Notable Commentary - DOI: 10.1016/j.bpj.2021.11.025.

Off

Traditional

White

Mo Gordon Wins 2020 SRAA Outstanding Poster Award

Anonymous — Fri, 06 Mar 2020 20:20:30 +0000

Mo Gordon Wins 2020 SRAA Outstanding Poster Award Anonymous (not verified) Fri, 03/06/2020 - 13:20

The Department of Biochemistry

Moshe Gordon, a Biochemistry graduate student in Dr. Joseph Falke's lab has been awarded the SRAA Outstanding Poster Award at the 2020 Biophysical Society Annual Conference in San Diego, California. Moshe presented his poster, titled "Single-Molecule Diffusion Studies of Membrane-bound PDK1-PKC Heterodimers Reveal a Monomee-Dimer Equilibrium with Regulatory Significance," during a graduate student competition and was one of two students selected from the Membrane Structure and Function category.

The Falke lab studies the leading-edge membrane of chemotaxing white blood cells. This highly specialized membrane possesses a sophisticated sensory pathway that enables white blood cells to follow chemical trails to sites of infection, inflammation, and tissue damage. The pathway includes multiple, membrane-bound master kinases responsible for integrating receptor and second messenger signals, ultimately yielding a signal output that controls the direction and speed of cell movement. In this project the lab measures the 2D diffusion, enzyme activities, and protein-protein interactions of single, membrane-bound kinase molecules via single molecule Total Internal Reflection Fluorescence microscopy (smTIRFM). In particular, Moshe's project focuses on elucidating the molecular mechanisms by which essential receptor-kinase and kinase-kinase interactions activate and inhibit the sensory pathway, respectively.

Falke Lab Biochem Research Graduate Program

Off

Traditional

White