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Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes

Oncogene volume 20, pages 1703–1714 (2001)Cite this article

Abstract

Immune cell-specific adaptor proteins create various combinations of multiprotein complexes and integrate signals from cell surface receptors to the nucleus, modulating the specificity and selectivity of intracellular signal transduction. Grap2 is a newly identified adaptor protein specifically expressed in lymphoid tissues. This protein shares 40–50% sequence homology in the SH3 and the SH2 domain with Grb2 and Grap. However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains. The expression of Grap2 is highly restricted to lymphoid organs and T lymphocytes. In order to understand the role of this specific adaptor protein in immune cell signaling and activation, we searched for the Grap2 interacting protein in T lymphocytes. We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells. The interaction was mediated by the carboxyl-terminal SH3 domain of Grap2 with the second proline-rich motif of HPK1. Coexpression of Grap2 with HPK1 not only increased the kinase activity of HPK1 in the cell, but also had an additive effect on HPK1 mediated JNK activation. Furthermore, over expression of Grap2 and HPK1 induced significant transcriptional activation of c-Jun in the JNK signaling pathway and IL-2 gene reporter activity in stimulated Jurkat T cells. Therefore, our data suggest that the hematopoietic specific proteins Grap2 and HPK1 form a signaling complex to mediate the c-Jun NH2-terminal kinase (JNK) signaling pathway in T cells.

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References

  • Anafi M, Kiefer F, Gish GD, Mbamalu G, Iscove NN, Pawson T . 1997 J. Biol. Chem. 272: 27804–27811

  • Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N, Takeshita T, Tsuchiya S, Konno T, Sugamura K . 1999 J. Exp. Med. 189: 1383–1390

  • Bourette RP, Arnaud S, Myles GM, Blanchet JP, Rohrschneider LR, Mouchiroud G . 1998 EMBO J. 17: 7273–7281

  • Bustelo XR . 2000 Mol. Cell. Biol. 20: 1461–1477

  • Cantrell DA . 1996 Cancer Surv. 27: 165–175

  • Chan AC, Dalton M, Johnson R, Kong GH, Wang T, Thoma R, Kurosaki T . 1995 EMBO J. 14: 2499–2508

  • Chan AC, Shaw AS . 1996 Curr. Opin. Immunol. 8: 394–401

  • Chen YR, Tan TH . 2000 Int. J. Oncol. 16: 651–662

  • Cheng AM, Saxton TM, Sakai R, Kulkarni S, Mbamalu G, Vogel W, Tortorice CG, Cardiff RD, Cross JC, Muller WJ, Pawson T . 1998 Cell 95: 793–803

  • Choi KY, Satterberg B, Lyons DM, Elion EA . 1994 Cell 78: 499–512

  • Clements JL, Boerth NJ, Lee JR, Koretzky GA . 1999 Annu. Rev. Immunol. 17: 89–108

  • Clements JL, Ross-Barta SE, Tygrett LT, Waldschmidt TJ, Koretzky GA . 1998a J. Immunol. 161: 3880–3889

  • Clements JL, Yang B, Ross-Barta SE, Eliason SL, Hrstka RF, Williamson RA, Koretzky GA . 1998b Science 281: 416–419

  • Clipstone NA, Crabtree GR . 1992 Nature 357: 695–697

  • Crabtree GR, Clipstone NA . 1994 Annu. Rev. Biochem. 63: 1045–1083

  • da Silva AJ, Li Z, de Vera C, Canto E, Findell P, Rudd CE . 1997 Proc. Natl. Acad. Sci. USA 94: 7493–7498

  • Deckert M, Tartare-Deckert S, Hernandez J, Rottapel R, Altman A . 1998 Immunity 9: 595–605

  • Diener K, Wang XS, Chen C, Meyer CF, Keesler G, Zukowski M, Tan TH, Yao Z . 1997 Proc. Natl. Acad. Sci. USA 94: 9687–9692

  • Donovan JA, Wange RL, Langdon WY, Samelson LE . 1994 J. Biol. Chem. 269: 22921–22924

  • Ellis JH, Ashman C, Burden MN, Kilpatrick KE, Morse MA, Hamblin PA . 2000 J. Immunol. 164: 5805–5814

  • Feng GS, Ouyang YB, Hu DP, Shi ZQ, Gentz R, Ni J . 1996 J. Biol. Chem. 271: 12129–12132

  • Fu C, Turck CW, Kurosaki T, Chan AC . 1998 Immunity 9: 93–103

  • Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH . 1996 Genes Dev. 10: 2251–2264

  • Hua SB, Qiu M, Chan E, Zhu L, Luo Y . 1997 Plasmid. 38: 91–96

  • Ip YT, Davis RJ . 1998 Curr. Opin. Cell. Biol. 10: 205–219

  • Jackman JK, Motto DG, Sun Q, Tanemoto M, Turck CW, Peltz GA, Koretzky GA, Findell PR . 1995 J. Biol. Chem. 270: 7029–7032

  • Karin M, Hunter T . 1995 Curr. Biol. 5: 747–757

  • Kiefer F, Tibbles LA, Anafi M, Janssen A, Zanke BW, Lassam N, Pawson T, Woodgett JR, Iscove NN . 1996 EMBO J. 15: 7013–7025

  • Law CL, Ewings MK, Chaudhary PM, Solow SA, Yun TJ, Marshall AJ, Hood L, Clark EA . 1999 J. Exp. Med. 189: 1243–1253

  • Ling P, Yao Z, Meyer CF, Wang XS, Oehrl W, Feller SM, Tan TH . 1999 Mol. Cell. Biol. 19: 1359–1368

  • Liou J, Kiefer F, Dang A, Hashimoto A, Cobb MH, Kurosaki T, Weiss A . 2000 Immunity 12: 399–408

  • Liu SK, Fang N, Koretzky GA, McGlade CJ . 1999 Curr. Biol. 9: 67–75

  • Liu SK, McGlade CJ . 1998 Oncogene 17: 3073–3082

  • Liu SK, Smith CA, Arnold R, Kiefer F, McGlade CJ . 2000 J. Immunol. 165: 1417–1426

  • Lowenstein EJ, Daly RJ, Batzer AG, Li W, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J . 1992 Cell 70: 431–442

  • Minden A, Karin M . 1997 Biochim. Biophys. Acta. 1333: F85–F104

  • Muegge K, Williams TM, Kant J, Karin M, Chiu R, Schmidt A, Siebenlist U, Young HA, Durum SK . 1989 Science 246: 249–251

  • Nagata Y, Kiefer F, Watanabe T, Todokoro K . 1999 Blood 93: 3347–3354

  • Northrop JP, Ullman KS, Crabtree GR . 1993 J. Biol. Chem. 268: 2917–2923

  • Oehrl W, Kardinal C, Ruf S, Adermann K, Groffen J, Feng GS, Blenis J, Tan TH, Feller SM . 1998 Oncogene 17: 1893–1901

  • Pappu R, Cheng AM, Li B, Gong Q, Chiu C, Griffin N, White M, Sleckman BP, Chan AC . 1999 Science 286: 1949–1954

  • Park DJ, Rho HW, Rhee SG . 1991 Proc. Natl. Acad. Sci. USA 88: 5453–5456

  • Pawson T . 1995 Nature 373: 573–580

  • Pivniouk V, Tsitsikov E, Swinton P, Rathbun G, Alt FW, Geha RS . 1998 Cell 94: 229–238

  • Qiu M, Hua S, Agrawal M, Li G, Cai J, Chan E, Zhou H, Luo Y, Liu M . 1998 Biochem. Biophys. Res. Commun. 253: 443–447

  • Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG . 1992 Nature 360: 689–692

  • Rudd CE . 1999 Cell 96: 5–8

  • Schneider H, Cai YC, Prasad KV, Shoelson SE, Rudd CE . 1995 Eur. J. Immunol. 25: 1044–1050

  • Songyang Z, Shoelson SE, McGlade J, Olivier P, Pawson T, Bustelo XR, Barbacid M, Sabe H, Hanafusa H, Yi T . 1994 Mol. Cell. Biol. 14: 2777–2785

  • Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben-Neriah Y . 1994 Cell 77: 727–736

  • Trub T, Frantz JD, Miyazaki M, Band H, Shoelson SE . 1997 J. Biol. Chem. 272: 894–902

  • Ullman KS, Northrop JP, Admon A, Crabtree GR . 1993 Genes Dev. 7: 188–196

  • Verweij CL, Guidos C, Crabtree GR . 1990 J. Biol. Chem. 265: 15788–15795

  • Wang W, Zhou G, Hu MCT, Yao Z, Tan TH . 1997 J. Biol. Chem. 272: 22771–22775

  • Wange RL, Guitian R, Isakov N, Watts JD, Aebersold R, Samelson LE . 1995 J. Biol. Chem. 270: 18730–18733

  • Wange RL, Samelson LE . 1996 Immunity 5: 197–205

  • Weber JR, Orstavik S, Torgersen KM, Danbolt NC, Berg SF, Ryan JC, Tasken K, Imboden JB, Vaage JT . 1998 J. Exp. Med. 187: 1157–1161

  • Weiss A, Koretzky G, Schatzman RC, Kadlecek T . 1991 Proc. Natl. Acad. Sci. USA 88: 5484–5488

  • Weiss A, Littman DR . 1994 Cell 76: 263–274

  • Whitmarsh AJ, Cavanagh J, Tournier C, Yasuda J, Davis RJ . 1998 Science 281: 1671–1674

  • Whitmarsh AJ, Davis RJ . 1998 Trends Biochem. Sci. 23: 481–485

  • Xia C, Bao Z, Tabassam F, Ma W, Qiu M, Hua S, Liu M . 2000 J. Biol. Chem. 275: 20942–20948

  • Zhang W, Samelson LE . 2000 Semin. Immunol. 12: 35–41

  • Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE . 1998 Cell 92: 83–92

  • Zhang W, Trible RP, Zhu M, Liu SK, McGlade CJ, Samelson LE . 2000 J. Biol. Chem. 275: 23355–23361

  • Zhou G, Lee SC, Yao Z, Tan TH . 1999 J. Biol. Chem. 274: 13133–13138

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Acknowledgements

This work was supported in part by a Scientist Development Grant 0030160N from the American Heart Association National and the Basil O'Connor Starter Scholar Research Award from March of Dimes Foundation (to M Liu) and NIH grants RO1-AI42532 and RO1-AI38649 (to T-H Tan).

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Authors and Affiliations

  1. Department of Medical Biochemistry and Genetics, Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 W. Holcombe Blvd., Texas, 77030, Houston, TX, USA

    Wenbin Ma, Chunzhi Xia & Mingyao Liu

  2. Department of Immunology, Baylor College of Medicine, 77030, Houston, Texas, TX, USA

    Pin Ling & Tse-Hua Tan

  3. Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, 40202, Kentucky, KY, USA

    Mengsheng Qiu

  4. Shanghai Genomics, Inc., Zhangjiang Hi-Tech Park, Pudong, Shangai 201204, P.R.C.

    Ying Luo

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Ma, W., Xia, C., Ling, P. et al. Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Oncogene 20, 1703–1714 (2001). https://doi.org/10.1038/sj.onc.1204224

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