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Jonathan M. Backer, M.D.

Jonathan M. Backer, M.D.

Professor, Department of Molecular Pharmacology

Chair Department of Molecular Pharmacology

William S. Lasdon Chair in Pharmacology Department of Molecular Pharmacology

Area of Research: Signal transduction; Phosphoinositide kinases; Tumor metastasis; Vesicular trafficking; macropinocytosis

Contact Information

718.430.2153718.430.3749jonathan.backer@einsteinmed.edu

Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 230
Bronx, NY 10461

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More Resources: Department of Molecular Pharmacology

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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 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 mutations in PI3Kbeta that block its binding to Gbeta-gamma inhibit the ability of both platelets and macrophages to stimulate the invasive behavior of tumor cells. Mutation of PI3Kbeta in macrophages also inhibits tumor cell production of IL8, a cytokine that promotes immune cell responses in primary tumors. Finally, we have shown that PI3Kbeta is essential for tumor cell macropinocytosis, a fluid-phase endocytic pathway that provides nutrients to support tumor growth. 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

Dbouk HA, Vadas O, Shymanets A, Burke JE, Salamon RS, Khalil BD, Barrett MO, Waldo GL, Surve C, Hsueh C, Perisic O, Harteneck C, Shepherd PR, Harden TK, Smrcka AV, Taussig R, Bresnick AR, Nürnberg B, Williams RL, Backer JM. G Protein–Coupled Receptor–Mediated Activation of p110β by Gβγ Is Required for Cellular Transformation and Invasiveness (2012) Science Signaling 5:ra89

Vadas, O, Dbouk, HA, Shymanets, A, Perisic, O, Abi Saab, WF, Khalil, BD, Burke, JE, Harteneck, C, Bresnick, AR, Nurnberg, B, Backer, JM, and Williams, RL. Molecular determinants of PI3Kγ-mediated chemotaxis and transformation downstream of GPCRs. (2013) PNAS 2013 110:18862-7. PMID:24190998

Khalil, BD, Hsueh, C., Cao, Y, Abi Saab, WF, Wang, Y, Condeelis, JS, Bresnick, AR and Backer, JM. (2016) GPCR signaling mediates tumor metastasis via PI3Kβ. Cancer Research 76:2944-2953

Erami, Z, Khalil, BD, Salloum, G, Yao, Y, LoPiccolo, J., Shymanets, A, Nurnberg, B, Bresnick AR, and Backer, JM. Rac1-Stimulated Macropinocytosis Enhances Gβγ Activation of PI3Kβ. (2017) Biochemical Journal 474:3903-3914.

Dulyaninova, N, Chang, A, Khalil, B., Backer, JM, and Bresnick, AR. S100A4 regulates podosomes and MMP9 secretion by distinct myosin-IIA dependent and independent mechanisms. (2018) Mol. Biol. Cell 29(5):632-642

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-kinaseβ is required for tumor cell invasion (2019) J. Biol. Chem 294:4621-4633.

Erami, Z., Heitz, SD. Bresnick AR, and Backer, JM. PI3Kβ links integrin activation and PI(3,4)P₂ production during invadopodial maturation (2019) Molecular Biology of the Cell 15:2367-2376.

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

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Faculty Profile

Jonathan M. Backer, M.D.

Contact Information

Professional Interests

SIGNALING BY PHOSPHOINOSITIDE KINASES

Selected Publications

Selected Publications

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