Photo of Alex Toker,  PhD

Alex Toker, PhD

Beth Israel Deaconess Medical Center

Beth Israel Deaconess Medical Center
Phone: (617) 735-2482
Fax: (617) 735-2480


atoker@bidmc.harvard.edu

Alex Toker, PhD

Beth Israel Deaconess Medical Center

EDUCATIONAL TITLES

  • Professor, Pathology, Harvard Medical School
  • Professor, Pathology, Beth Israel Deaconess Medical Center

DF/HCC PROGRAM AFFILIATION

Research Abstract

A major research focus in the laboratory is the regulation of carcinoma cell migration and invasion, with emphasis on the signaling pathways which impact this phenotype. Work in our laboratory has focused on transcription factors of the NFAT (Nuclear Factor of Activated T cells) family. We have found that NFATs are expressed and functionally active in cancer cells, and that NFAT transcriptional activity is required for promoting carcinoma invasion (Jauliac, NCB 2002). The significance of these studies is that they afford insight into a gene, NFAT, not previously known as being important for human carcinoma invasion and metastasis, and may thus provide a novel approach for targeted drug design for anti-tumor therapies. More recent studies have focused on the role of the Akt proto-oncogene in modulating breast cancer progression. We have discovered that Akt1 is breast cancer cell motility and invasion suppressor, a surprising finding considering that the PI 3-K and Akt pathway is clearly implicated in tumor progression (Yoeli-Lerner, Mol. Cell 2005). The significance of these findings is that small molecule inhibitors of Akt, currently being developed by many pharmaceutical companies, may actually enhance tumor invasion and metastasis. We have also discovered that a secreted variant of ADAM9, termed ADAM9-S, a member of the A Disintegrin And Metalloprotease family of matrix metalloproteases, is expressed and secreted by stromal cells in the tumor microenvironment, and promotes tumor invasion (Mazzocca, Can. Res. 2005). The current focus is to gain additional insight into the role of NFAT, Akt and ADAM9-S in invasion and migration, as well as genome-wide screens for genes induced by these pathways in carcinoma cells and the use of animal modes of invasion and metastasis to determine the importance of these proteins in the progression of the disease.

Another major research focus in the laboratory is the function of the serine/threonine kinase PKD (protein kinase D) in cancer cell biology. Our studies have shown that PKD is critical for the activation of the transcription factor NF-kB, leading to increased cellular survival in response to mitochondrial oxidative stress (Storz et al, MCB 2005). The significance of these results is that they describe a signaling pathway which cells use to increase their survival capacity under conditions of oxidative stress. ROS have been implicated in numerous human pathologies, including cancer, inflammation, Parkinson痴 disease, and are also believed to be major causative factors in human aging. Future goals include analysis of the mechanisms by which PKD regulates NF-kB and in particular the discovery of specific PKD substrates and how they relay signaling pathways. Thus, we have an active and long-term interest in kinase signaling and how it impacts downstream signaling pathways leading to cell growth, survival and motility.

Publications

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  • Brown KK, Montaser-Kouhsari L, Beck AH, Toker A. MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy. Cell Rep 2015; 11:1358-66. PubMed
  • Kaunisto A, Henry WS, Montaser-Kouhsari L, Jaminet SC, Oh EY, Zhao L, Luo HR, Beck AH, Toker A. NFAT1 promotes intratumoral neutrophil infiltration by regulating IL8 expression in breast cancer. Mol Oncol 2015. PubMed
  • Chin YM, Yuan X, Balk SP, Toker A. Pten-deficient tumors depend on akt2 for maintenance and survival. 2014. PubMed
  • Toker A, Chin YR. Akt-ing up on SRPK1: oncogene or tumor suppressor? Mol Cell 2014; 54:329-30. PubMed
  • Toker A, Marmiroli S. Signaling specificity in the Akt pathway in biology and disease. Adv Biol Regul 2014; 55C:28-38. PubMed
  • Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, Tsou P, Gan W, Papa A, Kim BM, Wan L, Singh A, Zhai B, Yuan M, Wang Z, Gygi SP, Lee TH, Lu KP, Toker A, Pandolfi PP, Asara JM, Kirschner MW, Sicinski P, Cantley L, Wei W. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014; 508:541-5. PubMed
  • Elloul S, Kedrin D, Knoblauch NW, Beck AH, Toker A. The adherens junction protein afadin is an AKT substrate that regulates breast cancer cell migration. Mol Cancer Res 2014; 12:464-76. PubMed
  • Chin YR, Yoshida T, Marusyk A, Beck AH, Polyak K, Toker A. Targeting Akt3 signaling in triple-negative breast cancer. Cancer Res 2014; 74:964-73. PubMed
  • White CD, Toker A. Using phospho-motif antibodies to determine kinase substrates. Curr Protoc Mol Biol 2013; Chapter 18:Unit 18.20.. PubMed
  • Kazerounian S, Gerald D, Huang M, Chin YR, Udayakumar D, Zheng N, O'Donnell RK, Perruzzi C, Mangiante L, Pourat J, Phung TL, Bravo-Nuevo A, Shechter S, McNamara S, Duhadaway JB, Kocher ON, Brown LF, Toker A, Prendergast GC, Benjamin LE. RhoB differentially controls Akt function in tumor cells and stromal endothelial cells during breast tumorigenesis. Cancer Res 2012. PubMed
  • Christoforides C, Rainero E, Brown KK, Norman JC, Toker A. PKD controls 留v硫3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5. Dev Cell 2012; 23:560-72. PubMed
  • Inuzuka H, Gao D, Finley LW, Yang W, Wan L, Fukushima H, Chin YR, Zhai B, Shaik S, Lau AW, Wang Z, Gygi SP, Nakayama K, Teruya-Feldstein J, Toker A, Haigis MC, Pandolfi PP, Wei W. Acetylation-dependent regulation of Skp2 function. Cell 2012; 150:179-93. PubMed
  • Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, Lawrence MS, Sivachenko AY, Sougnez C, Zou L, Cortes ML, Fernandez-Lopez JC, Peng S, Ardlie KG, Auclair D, Bautista-Piña V, Duke F, Francis J, Jung J, Maffuz-Aziz A, Onofrio RC, Parkin M, Pho NH, Quintanar-Jurado V, Ramos AH, Rebollar-Vega R, Rodriguez-Cuevas S, Romero-Cordoba SL, Schumacher SE, Stransky N, Thompson KM, Uribe-Figueroa L, Baselga J, Beroukhim R, Polyak K, Sgroi DC, Richardson AL, Jimenez-Sanchez G, Lander ES, Gabriel SB, Garraway LA, Golub TR, Melendez-Zajgla J, Toker A, Getz G, Hidalgo-Miranda A, Meyerson M. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 2012; 486:405-9. PubMed
  • Chin YR, Toker A. Akt2 regulates expression of the actin-bundling protein palladin. FEBS Lett 2010; 584:4769-74. PubMed
  • Fry JL, Toker A. Secreted and membrane-bound isoforms of protease ADAM9 have opposing effects on breast cancer cell migration. Cancer Res 2010; 70:8187-98. PubMed
  • Gao D, Wan L, Inuzuka H, Berg AH, Tseng A, Zhai B, Shaik S, Bennett E, Tron AE, Gasser JA, Lau A, Gygi SP, Harper JW, DeCaprio JA, Toker A, Wei W. Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. Mol Cell 2010; 39:797-808. PubMed
  • Nhek S, Ngo M, Yang X, Ng MM, Field SJ, Asara JM, Ridgway ND, Toker A. Regulation of OSBP Golgi Localization through Protein Kinase D-mediated Phosphorylation. Mol Biol Cell 2010; 21:2327-37. PubMed
  • Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell 2010; 38:333-44. PubMed
  • Toker A. TTC3 ubiquitination terminates Akt-ivation. Dev Cell 2010; 17:752-4. PubMed
  • Mancini M, Toker A. NFAT proteins: emerging roles in cancer progression. Nat Rev Cancer 2009; 9:810-20. PubMed
  • Storz P, Döppler H, Copland JA, Simpson KJ, Toker A. FOXO3a promotes tumor cell invasion through the induction of matrix metalloproteinases. Mol Cell Biol 2009; 29:4906-17. PubMed
  • Maurer M, Su T, Saal LH, Koujak S, Hopkins BD, Barkley CR, Wu J, Nandula S, Dutta B, Xie Y, Chin YR, Kim DI, Ferris JS, Gruvberger-Saal SK, Laakso M, Wang X, Memeo L, Rojtman A, Matos T, Yu JS, Cordon-Cardo C, Isola J, Terry MB, Toker A, Mills GB, Zhao JJ, Murty VV, Hibshoosh H, Parsons R. 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 2009; 69:6299-306. PubMed
  • Gao D,Inuzuka H,Tseng A,Chin RY,Toker A,Wei W. Phosphorylation by Akt1 promotes cytoplasmic localization of Skp2 and impairs APCCdh1-mediated Skp2 destruction. Nat Cell Biol 2009; 11:397-408. PubMed
  • Chin YR,Toker A. Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal 2008; 21:470-6. PubMed
  • Yoeli-Lerner M,Chin YR,Hansen CK,Toker A. Akt/protein kinase b and glycogen synthase kinase-3beta signaling pathway regulates cell migration through the NFAT1 transcription factor. Mol Cancer Res 2009; 7:425-32. PubMed
  • Watkins JL, Lewandowski KT, Meek SE, Storz P, Toker A, Piwnica-Worms H. Phosphorylation of the Par-1 polarity kinase by protein kinase D regulates 14-3-3 binding and membrane association. Proc Natl Acad Sci U S A 2008; 105:18378-83. PubMed
  • Toker A. Akt signaling: a damaging interaction makes good. Trends Biochem Sci 2008; 33:356-9. PubMed
  • Toker A. mTOR and Akt signaling in cancer: SGK cycles in. Mol Cell 2008; 31:6-8. PubMed
  • Kunkel MT, Toker A, Tsien RY, Newton AC. Calcium-dependent regulation of protein kinase D revealed by a genetically encoded kinase activity reporter. J Biol Chem 2006; 282:6733-42. PubMed
  • Yiu GK, Toker A. NFAT induces breast cancer cell invasion by promoting the induction of cyclooxygenase-2. J Biol Chem 2006; 281:12210-7. PubMed
  • Toker A, Yoeli-Lerner M. Akt signaling and cancer: surviving but not moving on. Cancer Res 2006; 66:3963-6. PubMed
  • Yoeli-Lerner M, Toker A. Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle 2006; 5:603-5. PubMed
  • Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 2005; 20:539-50. PubMed
  • Storz P, D. Protein kinase D mediates mitochondrion-to-nucleus signaling and detoxification from mitochondrial reactive oxygen species. Mol Cell Biol 2005; 25:8520-30. PubMed
  • Hausser A, Storz P, M. Protein kinase D regulates vesicular transport by phosphorylating and activating phosphatidylinositol-4 kinase IIIbeta at the Golgi complex. Nat Cell Biol 2005; 7:880-6. PubMed
  • Mazzocca A, Coppari R, De Franco R, Cho JY, Libermann TA, Pinzani M, Toker A. A secreted form of ADAM9 promotes carcinoma invasion through tumor-stromal interactions. Cancer Res 2005; 65:4728-38. PubMed
  • D. A phosphorylation state-specific antibody recognizes Hsp27, a novel substrate of protein kinase D. J Biol Chem 2005; 280:15013-9. PubMed
  • Storz P, D. Functional dichotomy of A20 in apoptotic and necrotic cell death. Biochem J 2004; 387:47-55. PubMed
  • Toker A. The biology and biochemistry of diacylglycerol signalling. Meeting on molecular advances in diacylglycerol signalling. EMBO Rep 2005; 6:310-4. PubMed
  • Hodges RR, Raddassi I, Zoukhri D, Toker A, Kazlauskas A, Dartt DA. Effect of overexpression of constitutively active PKCalpha on rat lacrimal gland protein secretion. Invest Ophthalmol Vis Sci 2004; 45:3974-81. PubMed
  • Hutti JE, Jarrell ET, Chang JD, Abbott DW, Storz P, Toker A, Cantley LC, Turk BE. A rapid method for determining protein kinase phosphorylation specificity. Nat Methods 2005; 1:27-9. PubMed
  • Storz P, D. Activation loop phosphorylation controls protein kinase D-dependent activation of nuclear factor kappaB. Mol Pharmacol 2004; 66:870-9. PubMed
  • Storz P, D. Protein kinase Cdelta selectively regulates protein kinase D-dependent activation of NF-kappaB in oxidative stress signaling. Mol Cell Biol 2004; 24:2614-26. PubMed
  • Storz P, D. Tyrosine phosphorylation of protein kinase D in the pleckstrin homology domain leads to activation. J Biol Chem 2003; 278:17969-76. PubMed
  • Storz P, Toker A. Protein kinase D mediates a stress-induced NF-kappaB activation and survival pathway. EMBO J 2002; 22:109-20. PubMed
  • Toker A. Identifying protein kinase C substrates: an introduction. Methods Mol Biol 2003; 233:247-51. PubMed
  • Toker A. Genetic manipulation of protein kinase C in vivo. Methods Mol Biol 2003; 233:475-89. PubMed
  • Storz P, Toker A. NF-kappaB signaling--an alternate pathway for oxidative stress responses. Cell Cycle 2003; 2:9-10. PubMed
  • Toker A. PDK-1 and protein kinase C phosphorylation. Methods Mol Biol 2003; 233:171-89. PubMed
  • Jauliac S, L. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 2002; 4:540-4. PubMed
  • Cenni V, D. Regulation of novel protein kinase C epsilon by phosphorylation. Biochem J 2002; 363:537-45. PubMed
  • Storz P, Toker A. 3'-phosphoinositide-dependent kinase-1 (PDK-1) in PI 3-kinase signaling. Front Biosci 2002; 7:d886-902. PubMed
  • Hodges RR, Kazlauskas A, Toker A, Dartt DA. Effect of overexpression of protein kinase C alpha on rat lacrimal gland protein secretion. Adv Exp Med Biol 2003; 506:237-41. PubMed
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