DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

Mitogenic/Oncogenic Signaling via Ras and the ERK-MAP kinase/RSK pathway.

The Mitogen-Activated Protein Kinases (or ERKs) and the ERK-regulated kinases (or RSKs) have been established as major participants in the regulation of cell proliferation and differentiation, but when improperly activated contribute to malignant transformation. Critical details regarding the regulation of this signaling system remain unclear. For example; what signals are responsible for the transient versus prolonged ERK/RSK activation and how does this translate into a cell context-dependent proliferation or differentiation response, what regulates the cytoplasmic and nuclear localization of these signaling enzymes, and how do these kinases regulate immediate-early gene expression? In addition, novel mitogen-regulated kinases activated downstream of the G-protein Ras are being characterized and their role in growth control investigated.


Mitogenic/Oncogenic Signaling via PI3-kinase and the p70-S6 Protein Kinase Pathway.

Together with the ERK/RSK pathway, the p70-S6 kinase signaling system is known to contribute to G1 cell cycle transition. The role of p70-S6 kinase in the regulation of protein translation and gene expression is being actively examined. A variety of signal transducing proteins have been shown to participate in p70-S6 kinase regulation. These include lipid-modifying enzymes such as phosphatidylinositol 3-kinase and PLCg, PI3-kinase-modulated kinases such as Akt/PKB, the phosphatidylinositol-like protein kinase FRAP/mTOR/RAFT, small G-proteins Cdc42 and Rac1, the proto-oncogenic exchange factors for these G proteins Dbl and TIAM-1 and the tumor suppressors, PTEN, TSC1/2, and LKB. How information from these various growth factor-regulated signal transducers and nutrient-sensing pathways converge to activate p70-S6 kinase is still unclear and is being investigated. Additional protein kinases are now being identified that participate in these signaling systems and their characterization is ongoing.


Protein Kinase Signaling Promoting Survival in Chemo-Resistant Tumor Cells.

We have completed an RNAi-based screen to identify kinases involved in promoting survival in cancer cells resistant to classical chemotherapeutics. All candidate targets are now being validated, characterized and evaluated as potential future targets for drug development.

Publications

• Holz MK, Ballif BA, Gygi SP, Blenis J.mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.Cell 2005 Nov 18;123(4):569-80.
  16286006
• Dimitri CA, Dowdle W, MacKeigan JP, Blenis J, Murphy LO.Spatially separate docking sites on ERK2 regulate distinct signaling events in vivo.Curr Biol 2005 Jul 26;15(14):1319-24.
  16051177
• MacKeigan JP, Murphy LO, Blenis J.Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.Nat Cell Biol 2005 Jun;7(6):591-600.
  15864305
• Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J.Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase.Proc Natl Acad Sci U S A 2004 Sep 14;101(37):13489-94.
  15342917
• Murphy LO, Smith S, Chen RH, Fingar DC, Blenis J.Molecular interpretation of ERK signal duration by immediate early gene products.Nat Cell Biol 2002 Aug;4(8):556-64.
  12134156
• Zhu J, Blenis J, Yuan J.Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1.Proc Natl Acad Sci U S A 2008 May 6;105(18):6584-9.
  18451027
• Ma XM, Yoon SO, Richardson CJ, Julich K, Blenis J.SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs.Cell 2008 Apr 18;133(2):303-13.
  18423201
• Yoon SO, Shin S, Liu Y, Ballif BA, Woo MS, Gygi SP, Blenis J.Ran-Binding Protein 3 Phosphorylation Links the Ras and PI3-Kinase Pathways to Nucleocytoplasmic Transport.Mol Cell 2008 Feb 15;29(3):362-75.
  18280241
• Mendoza MC, Blenis J.PHLPPing it off: phosphatases get in the Akt.Mol Cell 2007 Mar 23;25(6):798-800.
  17386258
• Roux PP, Shahbazian D, Vu H, Holz MK, Cohen MS, Taunton J, Sonenberg N, Blenis J.RAS/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation.J Biol Chem 2007 May 11;282(19):14056-64.
  17360704
• Zito CI, Qin H, Blenis J, Bennett AM.SHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathway.J Biol Chem 2007 Mar 9;282(10):6946-53.
  17229738
• Choo AY, Roux PP, Blenis J.Mind the GAP: Wnt steps onto the mTORC1 train.Cell 2006 Sep 8;126(5):834-6.
  16959561
• Shahbazian D, Roux PP, Mieulet V, Cohen MS, Raught B, Taunton J, Hershey JW, Blenis J, Pende M, Sonenberg N.The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.EMBO J 2006 Jun 21;25(12):2781-91.
  16763566
• Kim M, Lee JH, Koh H, Lee SY, Jang C, Chung CJ, Sung JH, Blenis J, Chung J.Inhibition of ERK-MAP kinase signaling by RSK during Drosophila development.EMBO J 2006 Jul 12;25(13):3056-67.
  16763554
• Hanrahan J, Blenis J.Rheb Activation of mTOR and S6K1 Signaling.Methods Enzymol 2005;407:542-55.
  16757352
• Liu L, Li F, Cardelli JA, Martin KA, Blenis J, Huang S.Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways.Oncogene 2006 May 22.
  16715128
• Murphy LO, Blenis J.MAPK signal specificity: the right place at the right time.Trends Biochem Sci 2006 May;31(5):268-75.
  16603362
• Choo AY, Blenis J.TORgeting oncogene addiction for cancer therapy.Cancer Cell 2006 Feb;9(2):77-9.
  16473275
• Lewthwaite JC, Bastow ER, Lamb KJ, Blenis J, Wheeler-Jones CP, Pitsillides AA.A specific mechanomodulatory role for p38 MAPK in embryonic joint articular surface cell MEK-ERK pathway regulation.J Biol Chem 2006 Apr 21;281(16):11011-8.
  16464862
• Anjum R, Roux PP, Ballif BA, Gygi SP, Blenis J.The Tumor Suppressor DAP Kinase Is a Target of RSK-Mediated Survival Signaling.Curr Biol 2005 Oct 11;15(19):1762-7.
  16213824
• Tee AR, Blenis J, Proud CG.Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1.FEBS Lett 2005 Aug 29;579(21):4763-8.
  16098514
• Holz MK, Blenis J.Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase.J Biol Chem 2005 Jul 15;280(28):26089-93.
  15905173
• Mackeigan JP, Murphy LO, Dimitri CA, Blenis J.Graded mitogen-activated protein kinase activity precedes switch-like c-Fos induction in mammalian cells.Mol Cell Biol 2005 Jun;25(11):4676-82.
  15899869
• Schalm SS, Tee AR, Blenis J.Characterization of a conserved C-terminal motif (RSPRR) in ribosomal protein S6 kinase 1 required for its mammalian target of rapamycin-dependent regulation.J Biol Chem 2005 Mar 25;280(12):11101-6.
  15659381
• Tee AR, Blenis J.mTOR, translational control and human disease.Semin Cell Dev Biol 2005 Feb;16(1):29-37.
  15659337
• Ballif BA, Roux PP, Gerber SA, MacKeigan JP, Blenis J, Gygi SP.Quantitative phosphorylation profiling of the ERK/p90 ribosomal S6 kinase-signaling cassette and its targets, the tuberous sclerosis tumor suppressors.Proc Natl Acad Sci U S A 2005 Jan 18;102(
  15647351
• Richardson CJ, Bröenstrup M, Fingar DC, Jülich K, Ballif BA, Gygi S, Blenis J.SKAR is a specific target of S6 kinase 1 in cell growth control.Curr Biol 2004 Sep 7;14(17):1540-9.
  15341740
• Richardson CJ, Schalm SS, Blenis J.PI3-kinase and TOR: PIKTORing cell growth.Semin Cell Dev Biol 2004 Apr;15(2):147-59.
  15209374
• Roux PP, Blenis J.ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions.Microbiol Mol Biol Rev 2004 Jun;68(2):320-44.
  15187187
• Fingar DC, Blenis J.Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression.Oncogene 2004 Apr 19;23(18):3151-71.
  15094765
• Tee AR, Tee JA, Blenis J.Characterizing the interaction of the mammalian eIF4E-related protein 4EHP with 4E-BP1.FEBS Lett 2004 Apr 23;564(1-2):58-62.
  15094042
• Woo MS, Ohta Y, Rabinovitz I, Stossel TP, Blenis J.Ribosomal S6 kinase (RSK) regulates phosphorylation of filamin A on an important regulatory site.Mol Cell Biol 2004 Apr;24(7):3025-35.
  15024089
• Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J.mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E.Mol Cell Biol 2004 Jan;24(1):200-16.
  14673156
• Murphy LO, MacKeigan JP, Blenis J.A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration.Mol Cell Biol 2004 Jan;24(1):144-53.
  14673150
• Tee AR, Manning BD, Roux PP, Cantley LC, Blenis J.Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.Curr Biol 2003 Aug 5;13(15):1259-68.
  12906785
• Tee AR, Anjum R, Blenis J.Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin.J Biol Chem 2003 Sep 26;278(39):37288-96.
  12867426
• Roux PP, Richards SA, Blenis J.Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity.Mol Cell Biol 2003 Jul;23(14):4796-804.
  12832467
• Schalm SS, Fingar DC, Sabatini DM, Blenis J.TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function.Curr Biol 2003 May 13;13(10):797-806.
  12747827
• Martin KA, Blenis J.Coordinate regulation of translation by the PI 3-kinase and mTOR pathways.Adv Cancer Res 2002;86:1-39.
  12374276
• 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
• Romanelli A, Dreisbach VC, Blenis J.Characterization of phosphatidylinositol 3-kinase-dependent phosphorylation of the hydrophobic motif site Thr(389) in p70 S6 kinase 1.J Biol Chem 2002 Oct 25;277(43):40281-9.
  12183455
• 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
• Fingar DC, Salama S, Tsou C, Harlow E, Blenis J.Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E.Genes Dev 2002 Jun 15;16(12):1472-87.
  12080086
• Schalm SS, Blenis J.Identification of a conserved motif required for mTOR signaling.Curr Biol 2002 Apr 16;12(8):632-9.
  11967149
• Richards SA, Dreisbach VC, Murphy LO, Blenis J.Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1.Mol Cell Biol 2001 Nov;21(21):7470-80.
  11585927
• Ballif BA, Blenis J.Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals.Cell Growth Differ 2001 Aug;12(8):397-408.
  11504705
• Ballif BA, Shimamura A, Pae E, Blenis J.Disruption of 3-phosphoinositide-dependent kinase 1 (PDK1) signaling by the anti-tumorigenic and anti-proliferative agent n-alpha-tosyl-l-phenylalanyl chloromethyl ketone.J Biol Chem 2001 Apr 13;276(15):12466-75.
  11278584
• Martin KA, Schalm SS, Romanelli A, Keon KL, Blenis J.Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation.J Biol Chem 2001
  11108720
• Martin KA, Schalm SS, Richardson C, Romanelli A, Keon KL, Blenis J.Regulation of ribosomal S6 kinase 2 by effectors of the phosphoinositide 3-kinase pathway.J Biol Chem 2001 Mar 16;276(11):7884-91.
  11108711
• Shimamura A, Ballif BA, Richards SA, Blenis J.Rsk1 mediates a MEK-MAP kinase cell survival signal.Curr Biol 2000 Feb 10;10(3):127-35.
  10679322
• Lee-Fruman KK, Kuo CJ, Lippincott J, Terada N, Blenis J.Characterization of S6K2, a novel kinase homologous to S6K1.Oncogene 1999 Sep 9;18(36):5108-14.
  10490847
• Richards SA, Fu J, Romanelli A, Shimamura A, Blenis J.Ribosomal S6 kinase 1 (RSK1) activation requires signals dependent on and independent of the MAP kinase ERK.Curr Biol 1999 Jul 29-Aug 12;9(15):810-20.
  10469565
• Romanelli A, Martin KA, Toker A, Blenis J.p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex.Mol Cell Biol 1999 Apr;19(4):2921-8.
  10082559
• Juo P, Kuo CJ, Yuan J, Blenis J.Essential requirement for caspase-8/FLICE in the initiation of the Fas-induced apoptotic cascade.Curr Biol 1998 Sep 10;8(18):1001-8.
  9740801
• Schinkmann K, Blenis J.Cloning and characterization of a human STE20-like protein kinase with unusual cofactor requirements.J Biol Chem 1997 Nov 7;272(45):28695-703.
  9353338
• Grammer TC, Blenis J.Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases.Oncogene 1997 Apr 10;14(14):1635-42.
  9135064
• Juo P, Kuo CJ, Reynolds SE, Konz RF, Raingeaud J, Davis RJ, Biemann HP, Blenis J.Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases.Mol Cell Biol 1997 Jan;17(1):24-35.
  8972182
• Grammer TC, Blenis J.The serine protease inhibitors, tosylphenylalanine chloromethyl ketone and tosyllysine chloromethyl ketone, potently inhibit pp70s6k activation.J Biol Chem 1996 Sep 27;271(39):23650-2.
  8798584
• Nakajima T, Fukamizu A, Takahashi J, Gage FH, Fisher T, Blenis J, Montminy MR.The signal-dependent coactivator CBP is a nuclear target for pp90RSK.Cell 1996 Aug 9;86(3):465-74.
  8756728
• Chou MM, Blenis J.The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1.Cell 1996 May 17;85(4):573-83.
  8653792