DF/HCC Program Affiliation

Gastrointestinal Malignancies
Lung Cancer
Prostate Cancer
Cancer Cell Biology

DF/HCC Associations

Deputy Associate Director, Basic Science, Executive Committee
Member, Center Scientific Council

Research Abstract

The major research objective of this laboratory is to understand the biochemical pathways that regulate normal mammalian cell growth and the defects that cause cell transformation. More than 10 years ago this laboratory discovered a phosphoinositide kinase that was activated by growth factor receptors and by oncoproteins. Further characterization of this enzyme revealed that it catalyzed an unexpected reaction, the phosphorylation of phosphatidylinositol at the D-3 position of the inositol ring (Whitman et al., 1988), thus leading to the discovery of a new signal transduction pathway. Subsequent research from this laboratory and other
laboratories showed that PI 3-kinase activation is critical for oncogene-mediated cell transformation, as well as for insulin-dependent stimulation of glucose uptake and metabolism. Recent work from this laboratory and other laboratories revealed that one of the products of PI 3-kinase directly activates the AKT/PKB protein kinase to provide a cell survival signal (Franke et al., 1997). A variety of proteins have evolved
domains that specifically interact with lipid products of the PI 3-kinase as a mechanism of regulated recruitment to cell membranes. The roles of these proteins in cell growth, cell migration and cell survival are under investigation. In addition, this laboratory has knocked out genes for subunits of PI 3-kinase in the mouse in order to better understand the importance of this enzyme in development, immunity and cancers. Another major focus of this laboratory is the structural basis for specificity in protein/protein interactions in signal transduction cascades. In particular, this laboratory has focused on the mechanism by which protein phosphorylation can control the assembly of signaling complexes. A novel oriented peptide library technique was developed to determine optimal phosphopeptides for binding to various protein domains (Songyang et al., 1993). This technique was subsequently modified to determine optimal substrates for protein kinases (Songyang et al., 1994,
1995, 1996). Through collaborations with other laboratories it has been possible to determine structures of protein-peptide complexes and thus explain how specificity in signaling is maintained (Yaffe et al., 1997a.b). These studies have also allowed predictions of intracellular targets of signaling proteins on the basis of primary sequence data banks.

Publications

• Esquibies AE, Bazzy-Asaad A, Ghassemi F, Nishio H, Karihaloo A, Cantley LG.VEGF Attenuates Hyperoxic Injury through Decreased Apoptosis in Explanted Rat Embryonic Lung.Pediatr Res 2008 Jan;63(1):20-5.
  18043510
• Asara JM, Schweitzer MH, Freimark LM, Phillips M, Cantley LC.Protein Sequences from Mastodon and Tyrannosaurus Rex Revealed by Mass Spectrometry.Science 2007 Apr 13;316(5822):280-285.
  17431180
• Asara JM, Zhang X, Zheng B, Maroney LA, Christofk HR, Wu N, Cantley LC.In-gel stable isotope labeling for relative quantification using mass spectrometry.Nat Protoc 2006;1(1):46-51.
  17406210
• Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, Cantley LC.Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha.Science 1999 Jan 15;283(5400):393-7.
  9888855
• Franke TF, Kaplan DR, Cantley LC, Toker A.Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate.Science 1997 Jan 31;275(5300):665-8.
  9005852
• Engelman JA, Cantley LC.A sweet new role for EGFR in cancer.Cancer Cell 2008 May;13(5):375-6.
  18455118
• Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC.The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.Nature 2008 Mar 13;452(7184):230-3.
  18337823
• Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC.Pyruvate kinase M2 is a phosphotyrosine-binding protein.Nature 2008 Mar 13;452(7184):181-6.
  18337815
• Asara JM, Christofk HR, Freimark LM, Cantley LC.A label-free quantification method by MS/MS TIC compared to SILAC and spectral counting in a proteomics screen.Proteomics 2008 Mar;8(5):994-9.
  18324724
• Lee JY, Engelman JA, Cantley LC.Biochemistry. PI3K charges ahead.Science 2007 Jul 13;317(5835):206-7.
  17626872
• Manning BD, Cantley LC.AKT/PKB signaling: navigating downstream.Cell 2007 Jun 29;129(7):1261-74.
  17604717
• Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Jänne PA.MET Amplification Leads to Gefitinib Resistance in Lu
  17463250
• Zheng B, Cantley LC.Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase.Proc Natl Acad Sci U S A 2007 Jan 16;104(3):819-22.
  17204563
• Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borrás AM, Gale CM, Naumov GN, Yeap BY, Jarrell E, Sun J, Tracy S, Zhao X, Heymach JV, Johnson BE, Cantley LC, Jänne PA.Allelic dilution obscures detection of a biologically significant resistance mutatio
  16906227
• Engelman JA, Luo J, Cantley LC.The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.Nat Rev Genet 2006 Aug;7(8):606-19.
  16847462
• Shaw RJ, Cantley LC.Ras, PI(3)K and mTOR signalling controls tumour cell growth.Nature 2006 May 25;441(7092):424-30.
  16724053
• Taniguchi CM, Kondo T, Sajan M, Luo J, Bronson R, Asano T, Farese R, Cantley LC, Kahn CR.Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta.Cell Metab 2006 May;3(5):343-53.
  16679292
• Pendaries C, Tronchère H, Arbibe L, Mounier J, Gozani O, Cantley L, Fry MJ, Gaits-Iacovoni F, Sansonetti PJ, Payrastre B.PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection.EMBO J 2006 Mar 8;25(5):1024-34.
  16482216
• Schulze H, Korpal M, Hurov J, Kim SW, Zhang J, Cantley LC, Graf T, Shivdasani RA.Characterization of the megakaryocyte demarcation membrane system and its role in thrombopoiesis.Blood 2006 May 15;107(10):3868-75.
  16434494
• Weiner OD, Rentel MC, Ott A, Brown GE, Jedrychowski M, Yaffe MB, Gygi SP, Cantley LC, Bourne HR, Kirschner MW.Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis.PLoS Biol 2006 Feb;4(2
  16417406
• Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS.Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells.Cancer Res 2005 Dec 1;65(23):10992-1000.
  16322248
• Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC.The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.Science 2005 Dec 9;310(5754):1642-6.
  16308421
• Grimm DH, Karihaloo A, Cai Y, Somlo S, Cantley LG, Caplan MJ.Polycystin-2 regulates proliferation and branching morphogenesis in kidney epithelial cells.J Biol Chem 2006 Jan 6;281(1):137-44.
  16278216
• Gozani O, Field SJ, Ferguson CG, Ewalt M, Mahlke C, Cantley LC, Prestwich GD, Yuan J.Modification of protein sub-nuclear localization by synthetic phosphoinositides: evidence for nuclear phosphoinositide signaling mechanisms.Adv Enzyme Regul 2005;45:171-8
  16199078
• Barbour LA, Mizanoor Rahman S, Gurevich I, Leitner JW, Fischer SJ, Roper MD, Knotts TA, Vo Y, McCurdy CE, Yakar S, Leroith D, Kahn CR, Cantley LC, Friedman JE, Draznin B.Increased P85alpha is a potent negative regulator of skeletal muscle insulin signalin
  16166093
• Luo J, Cantley LC.The negative regulation of phosphoinositide 3-kinase signaling by p85 and it's implication in cancer.Cell Cycle 2005 Oct;4(10):1309-12.
  16131837
• Karihaloo A, Karumanchi SA, Cantley WL, Venkatesha S, Cantley LG, Kale S.Vascular endothelial growth factor induces branching morphogenesis/tubulogenesis in renal epithelial cells in a neuropilin-dependent fashion.Mol Cell Biol 2005 Sep;25(17):7441-8.
  16107693
• Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, Halmos B, Pearlberg J, Tsuchihashi Z, Cantley LC, Tenen DG, Johnson BE, Jänne PA.Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth f
  16106023
• Field SJ, Madson N, Kerr ML, Galbraith KA, Kennedy CE, Tahiliani M, Wilkins A, Cantley LC.PtdIns(4,5)P2 functions at the cleavage furrow during cytokinesis.Curr Biol 2005 Aug 9;15(15):1407-12.
  16085494
• Luo J, Field SJ, Lee JY, Engelman JA, Cantley LC.The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex.J Cell Biol 2005 Aug 1;170(3):455-64.
  16043515
• Luo J, Sobkiw CL, Logsdon NM, Watt JM, Signoretti S, O'Connell F, Shin E, Shim Y, Pao L, Neel BG, Depinho RA, Loda M, Cantley LC.Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide
  16006513
• Keilhack H, David FS, McGregor M, Cantley LC, Neel BG.Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes.J Biol Chem 2005 Sep 2;280(35):30984-93.
  15987685
• Kang CM, Abbott DW, Park ST, Dascher CC, Cantley LC, Husson RN.The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape.Genes Dev 2005 Jul 15;19(14):1692-704.
  15985609
• Park J, Hu Y, Murthy TV, Vannberg F, Shen B, Rolfs A, Hutti JE, Cantley LC, Labaer J, Harlow E, Brizuela L.Building a human kinase gene repository: bioinformatics, molecular cloning, and functional validation.Proc Natl Acad Sci U S A 2005 Jun 7;102(23):81
  15928075
• Brachmann SM, Yballe CM, Innocenti M, Deane JA, Fruman DA, Thomas SM, Cantley LC.Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement.Mol Cell Biol 2005 Apr;25(7):2593-606.
  15767666
• Engelman JA, Jänne PA, Mermel C, Pearlberg J, Mukohara T, Fleet C, Cichowski K, Johnson BE, Cantley LC.ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines.Proc Natl Acad Sci U S A 2005 Mar 8;102(
  15731348
• Fernandes N, Sun Y, Chen S, Paul P, Shaw RJ, Cantley LC, Price BD.DNA damage-induced association of ATM with its target proteins requires a protein interaction domain in the N terminus of ATM.J Biol Chem 2005 Apr 15;280(15):15158-64.
  15713674
• Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC.The LKB1 tumor suppressor negatively regulates mTOR signaling.Cancer Cell 2004 Jul;6(1):91-9.
  15261145
• Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC.The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress.Proc Natl Acad Sci U S A 2004 Mar 9;101(10):3329-3
  14985505
• Gozani O, Karuman P, Jones DR, Ivanov D, Cha J, Lugovskoy AA, Baird CL, Zhu H, Field SJ, Lessnick SL, Villasenor J, Mehrotra B, Chen J, Rao VR, Brugge JS, Ferguson CG, Payrastre B, Myszka DG, Cantley LC, Wagner G, Divecha N, Prestwich GD, Yuan J.The PHD f
  12859901
• Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J.Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling.Proc Natl Acad Sci U S A 2002 Oct 15;99(2
  12271141
• Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC.Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.Mol Cell 2002 Jul;10(1):151-62.
  12150915
• Karpova AY, Trost M, Murray JM, Cantley LC, Howley PM.Interferon regulatory factor-3 is an in vivo target of DNA-PK.Proc Natl Acad Sci U S A 2002 Mar 5;99(5):2818-23.
  11867762
• Singh VP, Saluja AK, Bhagat L, van Acker GJ, Song AM, Soltoff SP, Cantley LC, Steer ML.Phosphatidylinositol 3-kinase-dependent activation of trypsinogen modulates the severity of acute pancreatitis.J Clin Invest 2001 Nov;108(9):1387-95.
  11696584
• Karuman P, Gozani O, Odze RD, Zhou XC, Zhu H, Shaw R, Brien TP, Bozzuto CD, Ooi D, Cantley LC, Yuan J.The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.Mol Cell 2001 Jun;7(6):1307-19.
  11430832
• Karumanchi SA, Jha V, Ramchandran R, Karihaloo A, Tsiokas L, Chan B, Dhanabal M, Hanai JI, Venkataraman G, Shriver Z, Keiser N, Kalluri R, Zeng H, Mukhopadhyay D, Chen RL, Lander AD, Hagihara K, Yamaguchi Y, Sasisekharan R, Cantley L, Sukhatme VP.Cell sur
  11336704
• Nishikawa K, Sawasdikosol S, Fruman DA, Lai J, Songyang Z, Burakoff SJ, Yaffe MB, Cantley LC.A peptide library approach identifies a specific inhibitor for the ZAP-70 protein tyrosine kinase.Mol Cell 2000 Oct;6(4):969-74.
  11090635
• Frangioni JV, LaRiccia LM, Cantley LC, Montminy MR.Minimal activators that bind to the KIX domain of p300/CBP identified by phage display screening.Nat Biotechnol 2000 Oct;18(10):1080-5.
  11017047
• Rittinger K, Budman J, Xu J, Volinia S, Cantley LC, Smerdon SJ, Gamblin SJ, Yaffe MB.Structural analysis of 14-3-3 phosphopeptide complexes identifies a dual role for the nuclear export signal of 14-3-3 in ligand binding.Mol Cell 1999 Aug;4(2):153-66.
  10488331
• Parker D, Jhala US, Radhakrishnan I, Yaffe MB, Reyes C, Shulman AI, Cantley LC, Wright PE, Montminy M.Analysis of an activator:coactivator complex reveals an essential role for secondary structure in transcriptional activation.Mol Cell 1998 Sep;2(3):353-9
  9774973
• Crovello CS, Lai C, Cantley LC, Carraway KL.Differential signaling by the epidermal growth factor-like growth factors neuregulin-1 and neuregulin-2.J Biol Chem 1998 Oct 9;273(41):26954-61.
  9756944
• Rameh LE, Rhee SG, Spokes K, Kazlauskas A, Cantley LC, Cantley LG.Phosphoinositide 3-kinase regulates phospholipase Cgamma-mediated calcium signaling.J Biol Chem 1998 Sep 11;273(37):23750-7.
  9726983
• Nishikawa K, Toker A, Wong K, Marignani PA, Johannes FJ, Cantley LC.Association of protein kinase Cmu with type II phosphatidylinositol 4-kinase and type I phosphatidylinositol-4-phosphate 5-kinase.J Biol Chem 1998 Sep 4;273(36):23126-33.
  9722541
• Tolias KF, Rameh LE, Ishihara H, Shibasaki Y, Chen J, Prestwich GD, Cantley LC, Carpenter CL.Type I phosphatidylinositol-4-phosphate 5-kinases synthesize the novel lipids phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 5-phosphate.J Biol Ch
  9660759
• Franke TF, Cantley LC.Apoptosis. A Bad kinase makes good.Nature 1997 Nov 13;390(6656):116-7.
  9367147
• Rameh LE, Tolias KF, Duckworth BC, Cantley LC.A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate.Nature 1997 Nov 13;390(6656):192-6.
  9367159
• Duckworth BC, Cantley LC.Conditional inhibition of the mitogen-activated protein kinase cascade by wortmannin. Dependence on signal strength.J Biol Chem 1997 Oct 31;272(44):27665-70.
  9346906
• Rameh LE, Arvidsson A, Carraway KL, Couvillon AD, Rathbun G, Crompton A, VanRenterghem B, Czech MP, Ravichandran KS, Burakoff SJ, Wang DS, Chen CS, Cantley LC.A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domain
  9268346
• Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK.Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase.Science 1997 Jun 20;276(5320):1848-50.
  9188528
• Toker A, Cantley LC.Signalling through the lipid products of phosphoinositide-3-OH kinase.Nature 1997 Jun 12;387(6634):673-6.
  9192891
• Wong K, Meyers ddR , Cantley LC.Subcellular locations of phosphatidylinositol 4-kinase isoforms.J Biol Chem 1997 May 16;272(20):13236-41.
  9148941
• Grabs D, Slepnev VI, Songyang Z, David C, Lynch M, Cantley LC, De Camilli P.The SH3 domain of amphiphysin binds the proline-rich domain of dynamin at a single site that defines a new SH3 binding consensus sequence.J Biol Chem 1997 May 16;272(20):13419-25.
  9148966
• Derman MP, Toker A, Hartwig JH, Spokes K, Falck JR, Chen CS, Cantley LC, Cantley LG.The lipid products of phosphoinositide 3-kinase increase cell motility through protein kinase C.J Biol Chem 1997 Mar 7;272(10):6465-70.
  9045671
• Franke TF, Kaplan DR, Cantley LC.PI3K: downstream AKTion blocks apoptosis.Cell 1997 Feb 21;88(4):435-7.
  9038334
• Meyers R, Cantley LC.Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase.J Biol Chem 1997 Feb 14;272(7):4384-90.
  9020160
• Songyang Z, Fanning AS, Fu C, Xu J, Marfatia SM, Chishti AH, Crompton A, Chan AC, Anderson JM, Cantley LC.Recognition of unique carboxyl-terminal motifs by distinct PDZ domains.Science 1997 Jan 3;275(5296):73-7.
  8974395
• Fruman DA, Cantley LC, Carpenter CL.Structural organization and alternative splicing of the murine phosphoinositide 3-kinase p85 alpha gene.Genomics 1996 Oct 1;37(1):113-21.
  8921377
• Panchamoorthy G, Fukazawa T, Miyake S, Soltoff S, Reedquist K, Druker B, Shoelson S, Cantley L, Band H.p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinase
  8621719