Faculty Profile

Dr. Jonathan M. Backer, M.D.

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

Areas of Research: Signal transduction Phosphoinositide kinases Actin/myosin and cell motility Tumor metastasis Vesicular trafficking

Professional Interests

SIGNALING BY PHOSPHOINOSITIDE KINASES

Phosphoinositide 3-kinases are lipid kinases that mediate signaling by receptor tyrosine kinases and G-protein coupled receptors (GPCRs). They are important regulators of cellular proliferation, motility, apoptosis, and vesicular trafficking. Mutational activation of PI 3-kinases is commonly found in human cancers. We are interested in how the altered regulation of PI 3-kinase contributes to human cancer. The Backer lab works collaboratively with the lab of Dr. Anne Bresnick, Dept. of Biochemistry, on all of these projects.

 1. GPCR-regulated PI 3-kinases in human cancer. The Class IA PI 3-kinase is a heterodimer composed of a catalytic subunit (p110) and a regulatory subunit (p85). Class IA PI 3-kinases are activated when p85 binds to phosphotyrosine residues in receptor tyrosine kinases and their substrates. The PI3Kb isoform of PI 3-kinase is unique in that it also directly binds to and is activated by Gbg subunits downstream of activated GPCRs. We have recently identified point mutants that specifically disrupt PI3Kb binding to Gbg, 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 PI3Kb regulates breast cancer invasion.

 2. PI 3-kinase regulation by Rab GTPases. The PI3Kb isoform of PI 3-kinase is also unique in that it specifically binds to the small GTPase Rab5, which regulates vesicular trafficking in the early endosome. We have mapped the Rab5 binding site in PI3Kb and produced mutants that are specifically defective for Rab5 binding. Cells expressing these mutants show a defect in some endocytic processes, as well as a disruption of autophagy in nutrient-starved cells. We are using knockdown/rescue methods in breast cancer cells, as well as mouse knock-in models, to define the mechanisms by which Rab5-PI3Kb binding regulates vesicular trafficking and responses to nutrient stress.

 3. PI 3-kinase - myosin signaling in macrophages. We are studying the regulation of macrophage motility and invasion. Mutation of PI3Kb inhibits the ability of macrophages to degrade extracellular matrix and cross endothelial layers. Interestingly, the phenotype of the mutant PI3Kb macrophages is similar to that caused by disruption of the myosin regulatory protein S100A4, and inhibitors of myosin activity rescue invasion in mutant PI3Kb macrophages. These data point to an novel interaction between PI3Kb and the myosin-based contractile apparatus. Using primary bone marrow-derived macrophages from mice expressing PI3Kb mutants, as well as macrophage cell lines, we are studying the links between PI3K and myosin signaling.

 

Selected Publications

Selected Publications 2012-18

 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 p110b by Gbg 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

Houslay, DM, Anderson, KE, Chessa, T, Kulkarni, S, Fritsch, R, Downward, J, Backer, JM, Stephens, LR, and Hawkins, PT. Co-incident signals from GPCRs and RTKs are uniquely transduced by PI3Kβ in myeloid cells. (2016) Science Signaling 9:ra82

Erami, Z, Khalil, BD, Salloum, G, Yao, Y, LoPiccolo, J., Shymanets, A, Nurnberg, B, Bresnick AR, and Backer, JM. Rac1-Stimulated Macropinocytosis Enhances Gbg 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

 

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Research Information