Forchheimer Building 230
Professor, Department of Molecular Pharmacology
Professor, Department of Biochemistry
Director, Belfer Institute for Advanced Biomedical Studies
SIGNALING BY PHOSPHOINOSITIDE KINASES
Phosphoinositide 3-kinases are lipid kinases that mediate signaling by tyrosine kinase and G-protein coupled receptors. PI 3-kinases are important regulators of cellular proliferation, motility, apoptosis, and vesicular trafficking. They are critical for insulin signaling, and are important in clinical diabetes. Mutational activation of PI 3-kinases is commonly found in human cancers. We are interested in the mechanisms that regulate PI 3'-kinase activity and the role of PI 3-kinases in intracellular signaling in diabetes, cancer and aging.
1. Activating mutations of PI 3-kinase in human cancer. The Class IA PI 3'-kinase is a heterodimer composed of a catalytic subunit (p110) and a regulatory subunit (p85). In normal cells, PI 3-kinase is activated when p85 binds to phosphotyrosine residues in receptor tyrosine kinases and their substrates, or when Gbg subunits from trimeric G-proteins bind to p110. p85 and p110 are frequently mutated in human breast, colon, prostate and brain cancer. Using biochemical, cell biological and biophysical methods, we are studying the mechanism of PI3K activation by both receptor tyrosine kinases and G-protein coupled receptors in normal cells, and how mutations in the regulatory and catalytic subunits of PI 3-kinase can lead to constitutive activity in cancer cells.
2. PI 3'-kinases in autophagy. Autophagy is a cellular response to nutrient deprivation in which cytosolic contents are engulfed and delivered to the lysosome for degradation. Autophagy is required for the viability of pancreatic beta cells, hepatocytes and neurons and for innate immune responses to pathogens. Downregulation of autophagic degradation has been implicated in neurodegenerative syndromes and in aging. The mammalian Class III PI 3-kinase, hVps34, plays essential roles in both vesicular trafficking and autophagy. We are studying the role of hVps34 in autophagy, and the mechanisms that regulate hVps34 activity, using both cell culture and animal models (mice and zebrafish).
3. PI 3'-kinases in tumor metastasis. Activating mutations of PI 3-kinases are frequently found in human breast cancer and other tumors. Using genetic methods, we have engineered human breast cancer cells to express physiological levels of wild type or mutant PI 3-kinase. We are studying the effects of the mutants on tumor metastasis in vivo, using xenograft tumors in SCID mice. We hope to uncover the mechanisms by which oncogenic PI 3-kinase mutations lead to enhanced metastasis.
Selected Publications 2010-
Flinn, RJ, Yan, Y, Goswami, S, Parker, PJ and Backer, JM. The late endosome is essential for mTORC1 signaling. (2010) Mol Biol Cell 21:833-841.
Sen, I, Wu, H. Backer, JM and Gerfen, GJ. The Structure of p85ni in Class IA PI 3-Kinase Exhibits Inter-Domain Disorder. (2010) Biochemistry 49:2159-2166.
Dbouk, HA, Pang, H, Fiser, A, and Backer, JM. A biochemical mechanism for the oncogenic potential of the p110b catalytic subunit of phosphoinositide 3-kinase. (2010) PNAS 107:19897-19902.
Bohdanowicz, M., Cosio, G., Backer J.M and Grinstein, S. Class I and class III phosphatidylinositol 3-kinases are required for actin polymerization that propels phagosomes. (2010) J. Cell Biol. 191:999-1012.
Smirnova, T. Zhou ZN, Flinn, RJ, Wyckoff, J, Boimel, PJ, Pozzuto, M, Coniglio, SJ, Backer, JM, Bresnick, AR, Condeelis JS, Hynes, NE and Segall, JE. Phosphoinositide 3-kinase signaling is critical for ErbB3-driven breast cancer cell motility and metastasis. (2011) Oncogene 31:706-715.
Yoon, MS, Du, G, Backer, JM, Frohman, MA and Chen, J. Class III PI 3-kinase activates phospholipase D in an amino acid-sensing mTORC1 pathway. (2011) J. Cell Biol. 195:435-447
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
Dou Z, Pan JA, Dbouk HA, Ballou LM, Deleon JL, Fan Y, Chen JS, Liang Z, Li G, Backer JM, Lin RZ, Zong WX. Class IA PI3K p110β Subunit Promotes Autophagy through Rab5 Small GTPase in Response to Growth Factor Limitation (2013) Mol. Cell 50:29-42.
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
Cao, Y, Chen, Y, Yang, F., Pessin, JE, and Backer, J.M. NRBF2 regulates autophagy as a component of Vps34 Complex 1. (2014) Biochemical J. (in press)