DF/HCC Program Affiliation

Cancer Cell Biology
Breast Cancer
Prostate Cancer

Research Abstract

Research in the Roberts laboratory is centered on the molecular mechanisms of signal transduction in response to activated tyrosine kinases. We pioneered structure/function studies on tyrosine kinases showing how tyrosine kinases such as pp60c-src are themselves regulated by tyrosine phosphorylation. The first definitive work on PI3'kinase was done by this lab in collaboration with that of Cantley and Schaffhausen. Similarly our lab first showed that the serine threonine kinase Raf-1 was regulated by mitogens and then helped to elucidate the pathway from p21ras to Raf to MAP kinases. More recently we first characterized the novel binding site used by the SHC protooncogene product to bind to receptors, and pointed out the interaction of the 14-3-3 molecules with key signal transducers. Finally we and our collaborators in the DeCaprio and Schaffhausen labs have showed how virus-encoded tumor antigens use molecular chaperones to direct the ubiquitin dependent degradation of phosphorylated forms of cell cycle control proteins. Currently we are working to clone and characterize new signaling molecules. The lab specializes in developing technologies for the study of signaling. These include the first synthetic gene for a tyrosine kinase (lck), the most widely used antiphosphotyrosine antibody, and the use of the zebrafish system for studying the role of signaling molecules in development.

Publications

• Gjoerup OV, Wu J, Chandler-Militello D, Williams GL, Zhao J, Schaffhausen B, Jat PS, Roberts TM.Surveillance mechanism linking Bub1 loss to the p53 pathway.Proc Natl Acad Sci U S A 2007 May 8.
  17488820
• Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y.The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases.Cell 2007 Mar 23;128(6):1077-88.
  17320160
• Zhao JJ, Roberts TM.PI3 kinases in cancer: from oncogene artifact to leading cancer target.Sci STKE 2006 Dec 12;2006(365):pe52.
  17164467
• Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A, Roberts TM.The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation.Proc Natl Acad Sci U S A 2006 Oct 31;103(44):16296-300.
  17060635
• Liu Z, Roberts TM.Human tumor mutants in the p110alpha subunit of PI3K.Cell Cycle 2006 Apr;5(7):675-7.
  16627990
• Bayliss PE, Bellavance KL, Whitehead GG, Abrams JM, Aegerter S, Robbins HS, Cowan DB, Keating MT, O'Reilly T, Wood JM, Roberts TM, Chan J.Chemical modulation of receptor signaling inhibits regenerative angiogenesis in adult zebrafish.Nat Chem Biol 2006 Ma
  16565716
• Qa'dan M, Christensen KA, Zhang L, Roberts TM, Collier RJ.Membrane insertion by anthrax protective antigen in cultured cells.Mol Cell Biol 2005 Jul;25(13):5492-8.
  15964805
• Zhang L, Gjoerup O, Roberts TM.The serine/threonine kinase cyclin G-associated kinase regulates epidermal growth factor receptor signaling.Proc Natl Acad Sci U S A 2004 Jul 13;101(28):10296-301.
  15240878
• Xia K, Lee RS, Narsimhan RP, Mukhopadhyay NK, Neel BG, Roberts TM.Tyrosine phosphorylation of the proto-oncoprotein Raf-1 is regulated by Raf-1 itself and the phosphatase Cdc25A.Mol Cell Biol 1999 Jul;19(7):4819-24.
  10373531
• Campbell KS, Mullane KP, Aksoy IA, Stubdal H, Zalvide J, Pipas JM, Silver PA, Roberts TM, Schaffhausen BS, DeCaprio JA.DnaJ/hsp40 chaperone domain of SV40 large T antigen promotes efficient viral DNA replication.Genes Dev 1997 May 1;11(9):1098-110.
  9159391
• Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM, Zhao JJ.Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis.Nature;454:776-9.
• Andrabi S, Gjoerup OV, Kean JA, Roberts TM, Schaffhausen B.Protein phosphatase 2A regulates life and death decisions via Akt in a context-dependent manner.Proc Natl Acad Sci U S A 2007 Nov 27;104(48):19011-6.
  18006659
• Goulart BH, Clark JW, Pien HH, Roberts TG, Finkelstein SN, Chabner BA.Trends in the use and role of biomarkers in phase I oncology trials.Clin Cancer Res 2007 Nov 15;13(22 Pt 1):6719-26.
  18006773
• Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y.A histone H3 lysine 27 demethylase regulates animal posterior development.Nature 2007 Oct 11;449(7163):689-94.
  17851529
• Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, Sjostrom SK, Garraway LA, Weremowicz S, Richardson AL, Greulich H, Stewart CJ, Mulvey LA, Shen RR, Ambrogio L, Hirozane-Kishikawa T, Hill DE, Vidal M, Meyerson M, Grenier JK, Hinkle G, Root DE, Rober
  17574021
• Utermark T, Schaffhausen BS, Roberts TM, Zhao JJ.The p110{alpha} isoform of PI3K is essential for polyoma middle T antigen mediated transformation.J Virol 2007 Apr 18.
  17442716
• Lin SS, Bassik MC, Suh H, Nishino M, Arroyo JD, Hahn WC, Korsmeyer SJ, Roberts TM.PP2A regulates BCL-2 phosphorylation and proteasome-mediated degradation at the endoplasmic reticulum.J Biol Chem 2006 May 22.
  16717086
• Zhao JJ, Liu Z, Wang L, Shin E, Loda MF, Roberts TM.The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells.Proc Natl Acad Sci U S A 2005 Dec 20;102(51):18443-8.
  16339315
• Westbrook TF, Martin ES, Schlabach MR, Leng Y, Liang AC, Feng B, Zhao JJ, Roberts TM, Mandel G, Hannon GJ, Depinho RA, Chin L, Elledge SJ.A genetic screen for candidate tumor suppressors identifies REST.Cell 2005 Jun 17;121(6):837-48.
  15960972
• Berger R, Febbo PG, Majumder PK, Zhao JJ, Mukherjee S, Signoretti S, Campbell KT, Sellers WR, Roberts TM, Loda M, Golub TR, Hahn WC.Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells.Cancer Res 2004 Dec 15;64(24):8867-7
  15604246
• Zhao JJ, Roberts TM, Hahn WC.Functional genetics and experimental models of human cancer.Trends Mol Med 2004 Jul;10(7):344-50.
  15242683
• Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM, Clardy J, Sellers WR, Silver PA.A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells.Cancer Ce
  14706338
• Zhao JJ, Gjoerup OV, Subramanian RR, Cheng Y, Chen W, Roberts TM, Hahn WC.Human mammary epithelial cell transformation through the activation of phosphatidylinositol 3-kinase.Cancer Cell 2003 May;3(5):483-95.
  12781366
• Chan J, Bayliss PE, Wood JM, Roberts TM.Dissection of angiogenic signaling in zebrafish using a chemical genetic approach.Cancer Cell 2002 Apr;1(3):257-67.
  12086862
• Kim HA, Ratner N, Roberts TM, Stiles CD.Schwann cell proliferative responses to cAMP and Nf1 are mediated by cyclin D1.J Neurosci 2001 Feb 15;21(4):1110-6.
  11160381
• Laham LE, Mukhopadhyay N, Roberts TM.The activation loop in Lck regulates oncogenic potential by inhibiting basal kinase activity and restricting substrate specificity.Oncogene 2000 Aug 17;19(35):3961-70.
  10962552
• Auger KR, Wang J, Narsimhan RP, Holcombe T, Roberts TM.Constitutive cellular expression of PI 3-kinase is distinct from transient expression.Biochem Biophys Res Commun 2000 Jun 16;272(3):822-9.
  10860837
• Kim HA, Pomeroy SL, Whoriskey W, Pawlitzky I, Benowitz LI, Sicinski P, Stiles CD, Roberts TM.A developmentally regulated switch directs regenerative growth of Schwann cells through cyclin D1.Neuron 2000 May;26(2):405-16.
  10839359
• Borghesani PR, Alt FW, Bottaro A, Davidson L, Aksoy S, Rathbun GA, Roberts TM, Swat W, Segal RA, Gu Y.Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice.Proc Natl Acad Sci U S A 2000 Mar 28;97(7):3336-41.
  10716718
• Gjoerup O, Chao H, DeCaprio JA, Roberts TM.pRB-dependent, J domain-independent function of simian virus 40 large T antigen in override of p53 growth suppression.J Virol 2000 Jan;74(2):864-74.
  10623749
• Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H.Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells.J Biol Chem 1999 Nov 5;274(45):32274-8.
  10542266
• Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR.Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway.Proc Natl Acad Sci U S A 1999 Mar 2;96
  10051603
• King FJ, Hu E, Harris DF, Sarraf P, Spiegelman BM, Roberts TM.DEF-1, a novel Src SH3 binding protein that promotes adipogenesis in fibroblastic cell lines.Mol Cell Biol 1999 Mar;19(3):2330-7.
  10022919
• Liu W, Su W, Roberts TM.Discovery of estrogen-responsive genes using an improved method which combines subtractive hybridization and PCR.Nucleic Acids Res 1998 Aug 1;26(15):3616-8.
  9671829
• Oliveira ML, Roberts TM, Druker BJ, Armelin MC.Mapping of polyomavirus middle T domain that is responsible for AP-1 activation.Oncogene 1998 Jun 11;16(23):2975-82.
  9662329
• Brownell HL, Lydon NB, Schaefer E, Roberts TM, Raptis L.Inhibition of epidermal growth factor-mediated ERK1/2 activation by in situ electroporation of nonpermeant [(alkylamino)methyl]acrylophenone derivatives.DNA Cell Biol 1998 Mar;17(3):265-74.
  9539106
• Batt DB, Roberts TM.Cell density modulates protein-tyrosine phosphorylation.J Biol Chem 1998 Feb 6;273(6):3408-14.
  9452462
• Culleré X, Rose P, Thathamangalam U, Chatterjee A, Mullane KP, Pallas DC, Benjamin TL, Roberts TM, Schaffhausen BS.Serine 257 phosphorylation regulates association of polyomavirus middle T antigen with 14-3-3 proteins.J Virol 1998 Jan;72(1):558-63.
  9420259
• Sheng Q, Denis D, Ratnofsky M, Roberts TM, DeCaprio JA, Schaffhausen B.The DnaJ domain of polyomavirus large T antigen is required to regulate Rb family tumor suppressor function.J Virol 1997 Dec;71(12):9410-6.
  9371601
• Stubdal H, Zalvide J, Campbell KS, Schweitzer C, Roberts TM, DeCaprio JA.Inactivation of pRB-related proteins p130 and p107 mediated by the J domain of simian virus 40 large T antigen.Mol Cell Biol 1997 Sep;17(9):4979-90.
  9271376
• 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
• Williams BP, Park JK, Alberta JA, Muhlebach SG, Hwang GY, Roberts TM, Stiles CD.A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells.Neuron 1997 Apr;18(4):553-62.
  9136765
• Luo H, Rose P, Barber D, Hanratty WP, Lee S, Roberts TM, D'Andrea AD, Dearolf CR.Mutation in the Jak kinase JH2 domain hyperactivates Drosophila and mammalian Jak-Stat pathways.Mol Cell Biol 1997 Mar;17(3):1562-71.
  9032284
• Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y.A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1.Mol Cell
  8943350
• Xia K, Mukhopadhyay NK, Inhorn RC, Barber DL, Rose PE, Lee RS, Narsimhan RP, D'Andrea AD, Griffin JD, Roberts TM.The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner.Proc Natl Acad Sci U S A 1996 Oct 15;93(21):11681-6.
  8876196
• Auger KR, Songyang Z, Lo SH, Roberts TM, Chen LB.Platelet-derived growth factor-induced formation of tensin and phosphoinositide 3-kinase complexes.J Biol Chem 1996 Sep 20;271(38):23452-7.
  8798552
• Nam HJ, Haser WG, Roberts TM, Frederick CA.Intramolecular interactions of the regulatory domains of the Bcr-Abl kinase reveal a novel control mechanism.Structure 1996 Sep 15;4(9):1105-14.
  8805596
• Jung JU, Lang SM, Jun T, Roberts TM, Veillette A, Desrosiers RC.Downregulation of Lck-mediated signal transduction by tip of herpesvirus saimiri.J Virol 1995 Dec;69(12):7814-22.
  7494293
• Jung JU, Lang SM, Friedrich U, Jun T, Roberts TM, Desrosiers RC, Biesinger B.Identification of Lck-binding elements in tip of herpesvirus saimiri.J Biol Chem 1995 Sep 1;270(35):20660-7.
  7544793