Jonathan M. Backer, M.D.
- Professor, Department of Molecular Pharmacology
- Professor, Department of Biochemistry
- Chair, Department of Molecular Pharmacology
- William S. Lasdon Chair in Pharmacology, Department of Molecular Pharmacology
- Associate Director, Shared Resources, Montefiore Einstein Comprehensive Cancer Center
Area of research
- Signal transduction; Phosphoinositide kinases; Tumor metastasis; Vesicular trafficking; macropinocytosis
Phone
Location
- Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Forchheimer Building 230 Bronx, NY 10461
Research Profiles
Professional Interests
SIGNALING BY PHOSPHOINOSITIDE KINASES
Phosphoinositide 3-kinases (PI3Ks) are lipid kinases that mediate signaling downstream from receptor tyrosine kinases and G-protein coupled receptors (GPCRs). They are important regulators of cellular proliferation, motility, apoptosis, and vesicular trafficking. Mutational activation of PI3Ks is commonly found in human cancers. We are interested in how the altered regulation of PI3K contributes to human cancer.
1. PI3Ks in breast cancer. Class I PI3Ks are the sole source of the signaling lipid phosphoinositide-3,4,5-P3 (PIP3) in cells, which activates downstream kinases like Akt, small GTPases like Rac and Cdc42, and signaling enzymes like Phospholipase C. The PI3Kbeta isoform of PI3K is unique among Class I PI3Ks in that it (a) is activated by binding to receptor tyrosine kinases, (b) is also activated by direct binding to Gbeta-gamma subunits downstream of activated GPCRs and to the small GTPase Rac1, and (c) specifically binds to the small GTPases Rab5, which regulates vesicular trafficking in the early endosome. We have identified point mutants that disrupt PI3Kbeta binding to either Gbeta-gamma or Rab5, and have shown that these mutants block tumor cell invasion in cell culture and animal models of breast cancer metastasis.
Our current work focusses on the mechanisms by which PI3Kbeta regulates breast cancer invasion, particularly its role in stromal cells such as macrophages and platelets. We have developed knock-in mice expressing the mutations that inhibit PI3Kbeta binding to either Gbeta-gamma or Rab5, and we are studying how these mutations affect the behavior of primary macrophages and platelets. We have shown that PI3Kbeta mutations inhibit the ability of both platelets and macrophages to stimulate the invasive behavior of tumor cells. In a parallel set of experiments, we have shown that mutation or knockout of PI3Kbeta in tumor cells inhibits invasion and metastasis, and also blocks macropinocytosis. This is a fluid-phase endocytic pathway that provides nutrients to support tumor growth under hypoxic or poorly vascularized conditions. Taken together, our findings suggest that PI3Kbeta could be an important drug target in the treatment of tumor growth and metastasis.
2. S100A4 signaling in macrophages. In collaboration with Dr. Anne Bresnick (Biochemistry), we are studying the regulation of cellular motility and invasion by the dimeric calcium-binding protein S100A4. S100A4 is prometastatic when expressed in tumor cells. We have recently found that S100A4 also regulates invasion and matrix degradation by both tumor cells and macrophages, and it is required for platelet stimulation of invasion by tumor cells. Our current work uses genomic, proteomic and cell biological methods to study how macrophage S100A4 regulates vesicular trafficking pathways that contribute to macrophage motility and invasion.
Selected Publications
Selected Publications
Jakubik, CT, Weckerly, CC, Hammond, GRV, Bresnick, AR, and Backer, JM. PIP3 abundance overcomes PI3K signaling selectivity in invadopodia. FEBS Letters 2022 596:417-426
Salloum, G., Jakubik, CT, Erami, Z., Heitz, SD, Bresnick, AR, and Backer, JM. PI3Kβ is selectively required for growth factor-stimulated micropinocytosis. (2019) J. Cell Sci. 132(16). pii: jcs231639
Heitz, SD, Hamelin, DJ, Hoffmann, RM, Greenbeerg, N, Salloum, G., Eramie, Z., Khalil, B., Shymanets,A, Steidle, EA, Gong, GQ, Nurrnberg, B, Burke, JE, Flanagan, JU, Bresnick, AR, and Backer, JM. A single discrete Rab5-binding site in phosphoinositide 3-kinase β is required for tumor cell invasion (2019) J. Biol. Chem 294:4621-4633.
Erami, Z., Heitz, SD. Bresnick AR, and Backer, JM. PI3K β links integrin activation and PI(3,4)P2 production during invadopodial maturation (2019) Molecular Biology of the Cell 15:2367-2376.