Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo)

Oncogene volume 20, pages 2197–2204 (2001)Cite this article

Abstract

In this study, we show that upon thrombopoietin (Tpo) stimulation the two adapter proteins Gab1 and Gab2 are strongly tyrosine phosphorylated and associated with Shc, SHP2, PI 3-kinase and Grb2 in mpl-expressing UT7 cells. Although Gab1 and Gab2 seem to mediate overlapping biological signals in many cells, only Gab1 is expressed and phosphorylated in response to Tpo in primary human megakaryocytic progenitors; furthermore, it associates with the same proteins. Although a low level of tyrosine phosphorylated IRS-2 protein is also detected in PI 3-kinase immunoprecipitates, Gab proteins are the essential proteins associated with PI 3-kinase after Tpo stimulation. We demonstrate that, albeit no association is detected between the Tpo receptor mpl and Gab proteins, Y112 located in the C-terminal cytoplasmic domain of mpl is required for Gab1/2 tyrosine phosphorylation. Gab proteins are not tyrosine phosphorylated after Tpo stimulation of UT-7 and Ba/F3 cells expressing a mpl mutant lacking Y112. Moreover, no activation of the PI 3-kinase/Akt pathway is observed in cells expressing this mpl mutant. Finally, we show that this mutant does not allow cell proliferation, thereby confirming that PI 3-kinase activation is required for Tpo-induced cell proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Alessi DR, Cohen P . 1998 Curr. Opin. Genet. Dev. 8: 55–62

  • Alexander WS, Maurer AB, Novak U, Harrison-Smith M . 1996 EMBO J. 15: 6531–6540

  • Bardelli A, Longati P, Gramaglia D, Stella MC, Comoglio PM . 1997 Oncogene 15: 3103–3111

  • Bartley TD, Bogenberger J, Hunt P, Li YS, Lu HS, Martin F, Chang MS, Samal B, Nichol JL, Swift S, Johnson MJ, Hsu RY, Parker VP, Suggs S, Skrine JD, Merewether LA, Clogston C, Hsu E, Hokom MM, Hornkohl A, Choi E, Pangelinan M, Sun Y, Mar V, McNinch J, Simonet L, Jacobsen F, Xie C, Shutter J, Chute H, Basu R, Selander L, Trollinger D, Sieu L, Padilla D, Trail G, Elliott G, Izumi R, Covey T, Crouse J, Garcia A, Xu W, Del Castillo J, Biron J, Cole S, Hu MCT, Pacifici R, Ponting I, Saris C, Wen D, Yung YP, Lin H, Bosselman RA . 1994 Cell 77: 1117–1124

  • Benit L, Courtois G, Charon M, Varlet P, Dusanter-Fourt I, Gisselbrecht S . 1994 J.Virol. 68: 5270–5274

  • Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B . 1997 Cell 88: 197–204

  • Case RD, Piccione E, Wolf G, Benett AM, Lechleider RJ, Neel BG, Shoelson SE . 1994 J. Biol. Chem. 269: 10467–10474

  • Damen JE, Liu L, Cutler RL, Krystal G . 1993 Blood 82: 2296–2303

  • de Sauvage FJ, Hass PE, Spencer SD, Malloy BE, Gurney AL, Spencer SA, Darbonne WC, Henzel WJ, Wong SC, Kuang WJ, Oles KJ, Hultgren B, Solberg Jr LA, Goeddel DV, Eaton DL . 1994 Nature 369: 533–538

  • Debili N, Coulombel L, Croisille L, Katz A, Guichard J, Breton-Gorius J, Vainchenker W . 1996 Blood 88: 1284–1296

  • Drachman JG, Griffin JD, Kaushansky K . 1995 J. Biol. Chem. 270: 4979–4982

  • Drachman JG, Kaushansky K . 1997 Proc. Natl. Acad. Sci. USA 94: 2350–2355

  • Dusanter-Fourt I, Casadevall N, Lacombe C, Muller O, Billat C, Fischer S, Mayeux P . 1992 J. Biol. Chem. 267: 10670–10675

  • Franke TF, Kaplan DR, Cantley LC . 1997 Cell 88: 435–437

  • Geltz NR, Augustine JA . 1998 Blood 91: 930–939

  • Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M, Nelson BH, Neel BG . 2000 Mol. Cell. Biol. 20: 7109–7120

  • Gu H, Pratt JC, Burakoff SJ, Neel BG . 1998 Mol. Cell 2: 729–740

  • Gurney AL, Wong SC, Henzel WJ, de Sauvage FJ . 1995 Proc. Natl. Acad. Sci. USA 92: 5292–5296

  • Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ . 1996 Nature 379: 560–564

  • Holgado-Madruga M, Moscatello DK, Emlet DR, Dieterich R, Wong AJ . 1997 Proc. Natl. Acad. Sci. USA 94: 12419–12424

  • Ingham RJ, Holgado-Madruga M, Siu C, Wong AJ, Gold MR . 1998 J. Biol. Chem. 273: 30630–30637

  • Itoh M, Yoshida Y, Nishida K, Narimatsu M, Hibi M, Hirano T . 2000 Mol. Cell. Biol. 20: 3695–3704

  • Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, Forstrom JW, Buddle MM, Oort PJ, Hagen FS, Roth GJ, Papayannopoulou T, Foster DC . 1994 Nature 369: 568–571

  • Korhonen JM, Said FA, Wong AJ, Kaplan DR . 1999 J. Biol. Chem. 274: 37307–37314

  • Laminet AA, Apell G, Conroy L, Kavanaugh WM . 1996 J. Biol. Chem. 271: 264–269

  • Lecoq-Lafon C, Verdier F, Fichelson S, Chretien S, Gisselbrecht S, Lacombe C, Mayeux P . 1999 Blood 93: 2578–2585

  • Lock LS, Royal I, Naujokas MA, Park M . 2000 J. Biol. Chem. 275: 31536–31545

  • Maroun CR, Holgado-Madruga M, Royal I, Naujokas MA, Fournier TM, Wong AJ, Park M . 1999 Mol. Cell. Biol. 19: 1784–1799

  • Matsumura I, Nakajima K, Wakao H, Hattori S, Hashimoto K, Sugahara H, Kato T, Miyazaki H, Hirano T, Kanakura Y . 1998 Mol. Cell. Biol. 18: 4282–4290

  • Miyakawa Y, Rojnuckarin P, Habib T, Kaushansky K . 2001 J. Biol. Chem. 276: 2494–2502

  • Nishida K, Yoshida Y, Itoh M, Fukada T, Ohtani T, Shirogane T, Atsumi T, Takahashi-Tezuka M, Ishihara K, Hibi M, Hirano T . 1999 Blood 93: 1809–1816

  • Pallard C, Gouilleux F, Benit L, Cocault L, Souyri M, Levy D, Groner B, Gisselbrecht S, Dusanter-Fourt I . 1995 EMBO J. 14: 2847–2856

  • Porteu F, Rouyez MC, Cocault L, Benit L, Charon M, Picard F, Gisselbrecht S, Souyri M, Dusanter-Fourt I . 1996 Mol. Cell. Biol. 16: 2473–2482

  • Raabe T, Riesgo-Escovar J, Liu X, Bausenwein BS, Deak P, Maroy P, Hafen E . 1996 Cell 85: 911–920

  • Rodrigues GA, Falasca M, Zhang Z, Ong SH, Schlessinger J . 2000 Mol. Cell. Biol. 20: 1448–1459

  • Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F . 1997 Mol. Cell. Biol. 17: 4991–5000

  • Sattler M, Durstin MA, Frank DA, Okuda K, Kaushansky K, Salgia R, Griffin JD . 1995 Exp. Hematol. 23: 1040–1048

  • Sattler M, Salgia R, Durstin MA, Prasad KV, Griffin JD . 1997 J. Cell Physiol. 171: 28–33

  • Shi ZQ, Yu DH, Park M, Marshall M, Feng GS . 2000 Mol. Cell. Biol. 20: 1526–1536

  • Songyang Z, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, Neel BG, Birge RB, Fajardo JE, Chou MM, Hanafusa H, Schaffhausen B, Cantley LC . 1993 Cell 72: 767–778

  • Takahashi-Tezuka M, Yoshida Y, Fukada T, Ohtani T, Yamanaka Y, Nishida K, Nakajima K, Hibi M, Hirano T . 1998 Mol. Cell. Biol. 18: 4109–4117

  • van der Geer P, Wiley S, Gish GD, Lai VK, Stephens R, White MF, Kaplan D, Pawson T . 1996 Proc. Natl. Acad. Sci. USA 93: 963–968

  • Vigon I, Florindo C, Fichelson S, Guenet JL, Mattei MG, Souyri M, Cosman D, Gisselbrecht S . 1993 Oncogene 8: 2607–2615

  • Vigon I, Mornon JP, Cocault L, Mitjavila MT, Tambourin P, Gisselbrecht S, Souyri M . 1992 Proc. Natl. Acad. Sci. USA 89: 5640–5644

  • Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J, Birchmeier W . 1996 Nature 384: 173–176

  • Wendling F, Maraskovsky E, Debili N, Florindo C, Teepe M, Titeux M, Methia N, Breton-Gorius J, Cosman D, Vainchenker W . 1994 Nature 369: 571–574

  • Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S, Sawyer ST, Krystal G, Yi T, Nishada K, Hibi M, Hirano T, Platanias LC . 1999 J. Biol. Chem. 274: 24469–24474

  • Yenush L, Makati KJ, Smith-Hall J, Ishibashi O, Myers Jr MG, White MF . 1996 J. Biol. Chem. 271: 24300–24306

  • Zhao C, Yu DH, Shen R, Feng GS . 1999 J. Biol. Chem. 274: 19649–19654

  • Zhou S, Cantley LC . 1995 Trends Biochem. Sci. 20: 470–475

Download references

Acknowledgements

The technical assistance of MC Rouyez and M Charon is gratefully acknowledged. We thank Dr Y Tanaka (Kirin, Japan) for the gift of recombinant human Tpo. We acknowledge the support of Janssen-Cilag Laboratories. This work was supported by grants from the Comité de Paris (Associate Laboratory #8) and the Comités de la Manche et de l'Aisne of the Ligue Nationale Contre le Cancer.

Author information

Authors and Affiliations

  1. Institut Cochin de Génétique Moléculaire (ICGM), Institut National de la Santé et de la Recherche Médicale (INSERM U363), Université René Descartes, France

    Didier Bouscary, Carinne Lecoq-Lafon, Stany Chrétien, Simona Zompi, Serge Fichelson, Odile Muller, Françoise Porteu, Isabelle Dusanter-Fourt, Sylvie Gisselbrecht, Patrick Mayeux & Catherine Lacombe

  2. Service d'Hématologie, AP-HP, Hôpital Cochin, France

    Didier Bouscary, Carinne Lecoq-Lafon & Catherine Lacombe

  3. Laboratoire de Recherche d'Hémobiologie. Site transfusionnel, Hôpital Cochin. 27 rue du Faubourg St Jacques, 75014, Paris, France

    Serge Fichelson

Authors
  1. Didier Bouscary
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carinne Lecoq-Lafon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stany Chrétien
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simona Zompi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Serge Fichelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Odile Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Françoise Porteu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isabelle Dusanter-Fourt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sylvie Gisselbrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Patrick Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Catherine Lacombe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bouscary, D., Lecoq-Lafon, C., Chrétien, S. et al. Role of Gab proteins in phosphatidylinositol 3-kinase activation by thrombopoietin (Tpo). Oncogene 20, 2197–2204 (2001). https://doi.org/10.1038/sj.onc.1204317

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204317

Keywords

This article is cited by

Search

Advanced search

Quick links