Rac1 mediates STAT3 activation by autocrine IL-6

July 24, 2001
98 (16) 9014-9019

Abstract

The activity of the small GTPase, Rac1, plays a role in various cellular processes including cytoskeletal rearrangement, gene transcription, and malignant transformation. In this report constitutively active Rac1 (Rac V12) is shown to stimulate the activation of STAT3, a member of the family of signal transducers and activators of transcription (STATs). The activity of Rac1 leads to STAT3 translocation to the nucleus coincident with STAT3-dependent gene expression. The expression of Vav (Δ1–187), a constitutively active guanine nucleotide exchange factor for the Rho GTPases, or activated forms of Ras or Rho family members, leads to STAT3-specific activation. The activation of STAT3 requires tyrosine phosphorylation at residue 705, but is not dependent on phosphorylation of Ser-727. Our studies indicate that Rac1 induces STAT3 activation through an indirect mechanism that involves the autocrine production and action of IL-6, a known mediator of STAT3 response. Rac V12 expression results in the induction of the IL-6 and IL-6 receptor genes and neutralizing antibodies directed against the IL-6 receptor block Rac1-induced STAT3 activation. Furthermore, inhibition of the nuclear factor-κB activation or disruption of IL-6-mediated signaling through the expression of IκBα S32AS36A and suppressor of cytokine signaling 3, respectively, blocks Rac1-induced STAT3 activation. These findings elucidate a mechanism dependent on the induction of an autocrine IL-6 activation loop through which Rac1 mediates STAT3 activation establishing a link between oncogenic GTPase activity and Janus kinase/STAT signaling.

Continue Reading

Acknowledgments

We thank Michael Hayman, Patrick Hearing, Todd Miller, and our laboratory colleagues for their helpful discussions. We also thank James Darnell, Jr., (The Rockefeller University) for STAT3 cDNA, Douglas Hilton (University of Melbourne) for SOCS-3 cDNA, Dean Ballard (Vanderbilt University) for IκBα S32AS36A cDNA, Steve McKnight (University of Texas Southwestern Medical Center) for STAT5a cDNA, and Rolf de Groot (University Hospital Utrecht) for STAT3β cDNA. This work was supported by Grants PO1CA28146 (to D.B. and N.C.R.) and RO1CA50773 from the National Institutes of Health and in part by a Carol M. Baldwin Breast Cancer Award (to N.C.R.) and by National Research Service Award funding (5T32DK07521) (to T.R.F.).

References

1
J E Darnell Science 277, 1630–1635 (1997).
2
C Schindler, J E Darnell Annu Rev Biochem 64, 621–651 (1995).
3
J N Ihle Nature (London) 377, 591–594 (1995).
4
W J Leonard, J J O'Shea Annu Rev Immunol 16, 293–322 (1998).
5
G R Stark, I M Kerr, B R Williams, R H Silverman, R D Schreiber Annu Rev Biochem 67, 227–264 (1998).
6
J F Bromberg, M H Wrzeszczynska, G Devgan, Y Zhao, R G Pestell, C Albanese, J E Darnell Cell 98, 295–303 (1999).
7
C L Yu, D J Meyer, G S Campbell, A C Larner, C Carter-Su, J Schwartz, R Jove Science 269, 81–83 (1995).
8
R Garcia, R Jove J Biomed Sci 5, 79–85 (1998).
9
D Besser, J F Bromberg, J E Darnell, H Hanafusa Mol Cell Biol 19, 1401–1409 (1999).
10
J Turkson, T Bowman, J Adnane, Y Zhang, J Y Djeu, M Sekharam, D A Frank, L B Holzman, J Wu, S Sebti, R Jove Mol Cell Biol 19, 7519–7528 (1999).
11
J J Schuringa, L J Jonk, W H Dokter, E Vellenga, W Kruijer Biochem J 347, 89–96 (2000).
12
S Uddin, F Lekmine, N Sharma, B Majchrzak, I Mayer, P R Young, G M Bokoch, E N Fish, L C Platanias J Biol Chem 275, 27634–27640 (2000).
13
A R Simon, H G Vikis, S Stewart, B L Fanburg, B H Cochran, K L Guan Science 290, 144–147 (2000).
14
L Van Aelst, C D'Souza-Schorey Genes Dev 11, 2295–2322 (1997).
15
J L Bos Cancer Res 49, 4682–4689 (1989).
16
R G Qiu, J Chen, D Kirn, F McCormick, M Symons Nature (London) 374, 457–459 (1995).
17
T Joneson, M McDonough, D Bar-Sagi, L Van Aelst Science 274, 1374–1376 (1996).
18
R G Qiu, A Abo, F McCormick, M Symons Mol Cell Biol 17, 3449–3458 (1997).
19
P Roux, C Gauthier-Rouviere, S Doucet-Brutin, P Fort Curr Biol 7, 629–637 (1997).
20
S Katzav, D Martin-Zanca, M Barbacid EMBO J 8, 2283–2290 (1989).
21
Z Zhong, Z Wen, J E Darnell Science 264, 95–98 (1994).
22
P C Heinrich, I Behrmann, G Muller-Newen, F Schaper, L Graeve Biochem J 334, 297–314 (1998).
23
O A Coso, M Chiariello, J C Yu, H Teramoto, P Crespo, N Xu, T Miki, J S Gutkind Cell 81, 1137–1146 (1995).
24
J A Brockman, D C Scherer, T A McKinsey, S M Hall, X Qi, W Y Lee, D W Ballard Mol Cell Biol 15, 2809–2818 (1995).
25
R Starr, T A Willson, E M Viney, L J Murray, J R Rayner, B J Jenkins, T J Gonda, W S Alexander, D Metcalf, N A Nicola, D J Hilton Nature (London) 387, 917–921 (1997).
26
M Wigler, A Pellicer, S Silverstein, R Axel, G Urlaub, L Chasin Proc Natl Acad Sci USA 76, 1373–1376 (1979).
27
H Kotanides, M Moczygemba, M F White, N C Reich J Biol Chem 270, 19481–19486 (1995).
28
T Joneson, M A White, M H Wigler, D Bar-Sagi Science 271, 810–812 (1996).
29
D Stokoe, S G Macdonald, K Cadwallader, M Symons, J F Hancock Science 264, 1463–1467 (1994).
30
X R Bustelo Mol Cell Biol 20, 1461–1477 (2000).
31
K E Schuebel, N Movilla, J L Rosa, X R Bustelo EMBO J 17, 6608–6621 (1998).
32
A Kaptein, V Paillard, M Saunders J Biol Chem 271, 5961–5964 (1996).
33
X Zhang, J Blenis, H C Li, C Schindler, S Chen-Kiang Science 267, 1990–1994 (1995).
34
Z Wen, Z Zhong, J E Darnell Cell 82, 241–250 (1995).
35
E Caldenhoven, T B van Dijk, R Solari, J Armstrong, J A M Raaijmakers, J W J Lammers, L Koenderman, R P de Groot J Biol Chem 271, 13221–13227 (1996).
36
J S Song, H Haleem-Smith, R Arudchandran, J Gomez, P M Scott, J F Mill, T H Tan, J Rivera J Immunol 163, 802–810 (1999).
37
R Brown, C J Marshall, S G Pennie, A Hall EMBO J 3, 1321–1326 (1984).
38
T A Libermann, D Baltimore Mol Cell Biol 10, 2327–2334 (1990).
39
D J Sulciner, K Irani, Z X Yu, V J Ferrans, P Goldschmidt-Clermont, T Finkel Mol Cell Biol 16, 7115–7121 (1996).
40
P A Baeuerle Cell 95, 729–731 (1998).
41
D Joyce, B Bouzahzah, M Fu, C Albanese, M D'Amico, J Steer, J U Klein, R J Lee, J E Segall, J K Westwick, et al. J Biol Chem 274, 25245–25249 (1999).
42
J R Grandis, S D Drenning, Q Zeng, S C Watkins, M F Melhem, S Endo, D E Johnson, L Huang, Y He, J D Kim Proc Natl Acad Sci USA 97, 4227–4232 (2000).
43
J Chung, E Uchida, T C Grammer, J Blenis Mol Cell Biol 17, 6508–6516 (1997).
44
Z Wen, J E Darnell Nucleic Acids Res 25, 2062–2067 (1997).
45
L K Schaefer, S Wang, T S Schaefer Biochem Biophys Res Commun 266, 481–487 (1999).
46
P Kovarik, M Mangold, K Ramsauer, H Heidari, R Steinborn, A Zotter, D E Levy, M Muller, T Decker EMBO J 20, 91–100 (2001).
47
M S Boguski, F McCormick Nature (London) 366, 643–654 (1993).
48
A Aronheim, D Engelberg, N Li, N al-Alawi, J Schlessinger, M Karin Cell 78, 949–961 (1994).

Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 98 | No. 16
July 31, 2001
PubMed: 11470914

Classifications

Submission history

Received: March 2, 2001
Accepted: June 5, 2001
Published online: July 24, 2001
Published in issue: July 31, 2001

Acknowledgments

We thank Michael Hayman, Patrick Hearing, Todd Miller, and our laboratory colleagues for their helpful discussions. We also thank James Darnell, Jr., (The Rockefeller University) for STAT3 cDNA, Douglas Hilton (University of Melbourne) for SOCS-3 cDNA, Dean Ballard (Vanderbilt University) for IκBα S32AS36A cDNA, Steve McKnight (University of Texas Southwestern Medical Center) for STAT5a cDNA, and Rolf de Groot (University Hospital Utrecht) for STAT3β cDNA. This work was supported by Grants PO1CA28146 (to D.B. and N.C.R.) and RO1CA50773 from the National Institutes of Health and in part by a Carol M. Baldwin Breast Cancer Award (to N.C.R.) and by National Research Service Award funding (5T32DK07521) (to T.R.F.).

Authors

Affiliations

Tatjana R. Faruqi
Departments of Pathology and Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; and Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain
Dolores Gomez
Departments of Pathology and Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; and Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain
Xosé R. Bustelo
Departments of Pathology and Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; and Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain
Dafna Bar-Sagi
Departments of Pathology and Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; and Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain
Nancy C. Reich§
Departments of Pathology and Molecular Genetics and Microbiology, State University of New York, Stony Brook, NY 11794; and Centro de Investigación del Cáncer, University of Salamanca, 37007 Salamanca, Spain

Notes

§
To whom reprint requests should be addressed. E-mail: [email protected].
Communicated by William J. Lennarz, State University of New York, Stony Brook, NY

Metrics & Citations

Metrics

Note: The article usage is presented with a three- to four-day delay and will update daily once available. Due to ths delay, usage data will not appear immediately following publication. Citation information is sourced from Crossref Cited-by service.


Citation statements

Altmetrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.

Cited by

    Loading...

    View Options

    View options

    PDF format

    Download this article as a PDF file

    DOWNLOAD PDF

    Get Access

    Login options

    Check if you have access through your login credentials or your institution to get full access on this article.

    Personal login Institutional Login

    Recommend to a librarian

    Recommend PNAS to a Librarian

    Purchase options

    Purchase this article to get full access to it.

    Single Article Purchase

    Rac1 mediates STAT3 activation by autocrine IL-6
    Proceedings of the National Academy of Sciences
    • Vol. 98
    • No. 16
    • pp. 8923-9464

    Media

    Figures

    Tables

    Other

    Share

    Share

    Share article link

    Share on social media