Forchheimer Building 230
Professor, Department of Molecular Pharmacology
Professor, Department of Biochemistry
William S. Lasdon Chair in Pharmacology
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 the 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 p85/p110β isoform of PI 3-kinase is unique in that it also directly binds to and is regulated by Gβγ subunits downstream of activated GPCRs. We have recently identified point mutants that specifically disrupt p110β binding to Gβγ, and have shown that these mutants disrupt p110β-mediated transformation, invasion, and tumorigenesis. We are studying the role of Gβγ-regulated signaling by p110β in cell culture and animal models. We are focusing of p110β signaling in breast cancer metastasis and in PTEN-null prostate cancer. These studies will be important for understanding the role of GPCR-regulated PI 3-kinase signaling in human cancer.
2. PI 3-kinase regulation by Rab GTPases. The p110β isoform of PI 3-kinase is also unique in that it specifically binds to the endosomal GTPase Rab5, which regulates vesicular trafficking in the early endosome. We have mapped the Rab5 binding site in p110β 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 and prostate cancer cells, as well as mouse knock-in models, to define the mechanisms by which Rab5-p110β binding regulates vesicular trafficking and responses to nutrient stress.
3. 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, with a focus on identifying novel regulators of Vps34 activity and targeting.
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.
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.
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. 461:315-322.