Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism (original) (raw)

• Brief Communication
• Published: 22 July 2002
• Que T. Lambert1,2,
• Gary W. Reuther1,2,
• Angeliki Malliri3,
• David P. Siderovski1,2,4,
• John Sondek1,2,5,
• John G. Collard3 &
• …
• Channing J. Der1,2

Nature Cell Biology volume 4, pages 621–625 (2002)Cite this article

• 2374 Accesses
• 253 Citations
• 8 Altmetric
• Metrics details

Abstract

Rac is a member of the Ras superfamily of GTPases and functions as a GDP/GTP-regulated switch1. Formation of active Rac-GTP is stimulated by Dbl family guanine nucleotide exchange factors (GEFs), such as Tiam1 (ref. 2). Once activated, Rac stimulates signalling pathways that regulate actin organization, gene expression and cellular proliferation. Rac also functions downstream of the Ras oncoprotein in pathways that stimulate membrane ruffling3, growth transformation4,5, activation of the c-Jun amino-terminal kinase (JNK) mitogen-activated protein kinase6, activation of the NF-κB transcription factor and promotion of cell survival7,8. Although recent studies support phosphatidylinositol 3-OH kinase (PI(3)K)-dependent mechanisms through which Ras might activate Rac (refs 9,10), the precise mechanism remains to be determined. Here we demonstrate that Tiam1, a Rac-specific GEF, preferentially associates with activated GTP-bound Ras through a Ras-binding domain. Furthermore, activated Ras and Tiam1 cooperate to cause synergistic formation of Rac-GTP in a PI(3)K-independent manner. Thus, Tiam1 can function as an effector that directly mediates Ras activation of Rac.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

• Purchase on SpringerLink
• Instant access to full article PDF

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

Additional access options:

• Log in
• Learn about institutional subscriptions
• Read our FAQs
• Contact customer support

Similar content being viewed by others

References

1. Bar-Sagi, D. & Hall, A. Cell 103, 227–238 (2000).
   Article CAS Google Scholar
2. Zheng, Y. Trends Biochem. Sci. 26, 724–732 (2001).
   Article CAS Google Scholar
3. Ridley, A. J., Paterson, H. F., Johnston,C. L., Diekmann, D. & Hall, A. Cell 70, 401–410 (1992).
   Article CAS Google Scholar
4. Qiu, R.-G., Chen, J., Kirn, D., McCormick, F. & Symons, M. Nature 374, 457–459 (1995).
   Article CAS Google Scholar
5. Khosravi-Far, R., Solski, P. A., Kinch, M. S., Burridge, K. & Der, C. J. Mol. Cell. Biol. 15, 6443–6453 (1995).
   Article CAS Google Scholar
6. Minden, A., Lin, A., Claret, F.-X., Abo, A. & Karin, M. Cell 81, 1147–1157 (1995).
   Article CAS Google Scholar
7. Sulciner, D. J. et al. Mol. Cell. Biol. 16, 7115–7121 (1996).
   Article CAS Google Scholar
8. Joneson, T. & Bar-Sagi, D. Mol. Cell. Biol. 19, 5892–5901 (1999).
   Article CAS Google Scholar
9. Nimnual, A. S., Yatsula, B. A. & Bar-Sagi, D. Science 279, 560–563 (1998).
   Article CAS Google Scholar
10. Scita, G. et al. Nature 401, 290–293 (1999).
    Article CAS Google Scholar
11. Worthylake, D. K., Rossman, K. L. & Sondek, J. Nature 408, 682–688 (2000).
    Article CAS Google Scholar
12. Ponting, C. P. J. Mol. Med. 77, 695–698 (1999).
    Article CAS Google Scholar
13. Bar-Sagi, D. & Feramisco, J. R. Science 233, 1061–1068 (1986).
    Article CAS Google Scholar
14. Rodriguez-Viciana, P. et al. Cell 89, 457–467 (1997).
    Article CAS Google Scholar
15. Zondag, G. C. et al. J. Cell Biol. 149, 775–782 (2000).
    Article CAS Google Scholar
16. Adari, H., Lowy, D. R., Willumsen, B. M., Der, C. J. & McCormick, F. Science 240, 518–521 (1988).
    Article CAS Google Scholar
17. Reuther, G. W. et al. J. Biol Chem. (in the press).
18. Peterson, S. N. et al. J. Biol. Chem. 271, 29903–29908 (1996).
    Article CAS Google Scholar
19. Fabian, J. R., Vojtek, A. B., Cooper, J. A. & Morrison, D. K. Proc. Natl Acad. Sci. USA 91, 5982–5986 (1994).
    Article CAS Google Scholar
20. Nassar, N. et al. Nature 375, 554–560 (1995).
    Article CAS Google Scholar
21. Han, J. et al. Science 279, 558–560 (1998).
    Article CAS Google Scholar
22. Fleming, I. N., Gray, A. & Downes, C. P. Biochem. J. 351, 173–182 (2000).
    Article CAS Google Scholar
23. Murphy, G. A. et al. J. Biol. Chem. 277, 9966–9975 (2002).
    Article CAS Google Scholar
24. Crompton, A. M. et al. J. Biol. Chem. 275, 25751–25759 (2000).
    Article CAS Google Scholar
25. Snyder, J. T. et al. J. Biol. Chem. 276, 45868–45875 (2001).
    Article CAS Google Scholar
26. Malliri, A. et al. Nature 417, 867–871 (2002).
    Article CAS Google Scholar
27. Chang, E. C. et al. Cell 79, 131–141 (1994).
    Article CAS Google Scholar
28. Westwick, J. K. et al. Mol. Cell. Biol. 17, 1324–1335 (1997).
    Article CAS Google Scholar
29. Altschul, S. F. et al. Nucleic Acids Res. 25, 3389–3402 (1997).
    Article CAS Google Scholar
30. Fischer, D. et al. Proteins 3, S209–S217 (1999).
    Article Google Scholar

Download references

Acknowledgements

We thank C.I. Behe and M. Pham for technical assistance, and M. Rand for assistance in figure and manuscript preparation. We thank M. Ostrowski, G. Bollag, J. Downward, C. Hauser and B. Mayer for plasmid constructs. This work was supported by grants from the National Institutes of Health to D.P.S. (GM62338), J.S.(GM62299), and C.J.D. (CA69577), as well as a career award from the Pew Charitable Trusts (J.S.). G.W.R. is a Leukemia and Lymphoma Society Special Fellow. D.P.S. is a Year 2000 Scholar of the EJLB Foundation and a recipient of the Burroughs-Wellcome New Investigator Award in the Basic Pharmacological Sciences. Part of this work was supported by the Dutch Cancer Society, the European Community and the Association for International Cancer Research (J.G.C.).

Author information

Authors and Affiliations

1. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA
   John M. Lambert, Que T. Lambert, Gary W. Reuther, David P. Siderovski, John Sondek & Channing J. Der
2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA
   John M. Lambert, Que T. Lambert, Gary W. Reuther, David P. Siderovski, John Sondek & Channing J. Der
3. Division of Cell Biology, The Netherlands Cancer Institute, Plesmaniaan 121, Amsterdam, 1066, CX, The Netherlands
   Angeliki Malliri & John G. Collard
4. UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA
   David P. Siderovski
5. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA
   John Sondek

Authors

1. John M. Lambert
   You can also search for this author inPubMed Google Scholar
2. Que T. Lambert
   You can also search for this author inPubMed Google Scholar
3. Gary W. Reuther
   You can also search for this author inPubMed Google Scholar
4. Angeliki Malliri
   You can also search for this author inPubMed Google Scholar
5. David P. Siderovski
   You can also search for this author inPubMed Google Scholar
6. John Sondek
   You can also search for this author inPubMed Google Scholar
7. John G. Collard
   You can also search for this author inPubMed Google Scholar
8. Channing J. Der
   You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toChanning J. Der.

Rights and permissions

About this article

Cite this article

Lambert, J., Lambert, Q., Reuther, G. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism.Nat Cell Biol 4, 621–625 (2002). https://doi.org/10.1038/ncb833

Download citation

• Received: 12 September 2001
• Revised: 12 June 2002
• Accepted: 01 July 2002
• Published: 22 July 2002
• Issue Date: 01 August 2002
• DOI: https://doi.org/10.1038/ncb833

This article is cited by