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:

Homo- and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential

Oncogene volume 23, pages 233–240 (2004)Cite this article

Abstract

PDZ-RhoGEF, LARG, and p115RhoGEF are members of a newly identified family of Rho-guanine nucleotide exchange factors (GEFs) exhibiting a unique structural feature consisting of the presence of an area of similarity to regulators of G protein signaling (RGS). This RGS-like (RGL) domain provides a functional motif by which Gα12 and Gα13 can bind and regulate the activity of these RhoGEFs, thus providing a direct link from these heterotrimeric G proteins to Rho. PDZ-RhoGEF and LARG can also be phosphorylated by tyrosine kinases, including FAK, and associate with Plexin B, a semaphorin receptor, which controls axon guidance during development, through their PDZ domain, thereby stimulating Rho. Interestingly, while characterizing a PDZ-RhoGEF antiserum, we found that a transfected PDZ-RhoGEF construct associated with the endogenous PDZ-RhoGEF. Indeed, we observed that PDZ-RhoGEF and LARG can form homo- and hetero-oligomers, whereas p115RhoGEF can only homo-oligomerize, and that this intermolecular interaction was mediated by their unique C-terminal regions. Deletion of the C-terminal tail of PDZ-RhoGEF had no significant effect on the GEF catalytic activity towards Rho in vitro, but resulted in a drastic increase in the ability to stimulate a serum response element reporter and the accumulation of the GTP-bound Rho in vivo. Furthermore, removal of the C-termini of each of the three RGL-containing GEFs unleashed their full transforming potential. Together, these findings suggest the existence of a novel mechanism controlling the activity of PDZ-RhoGEF, LARG, and p115RhoGEF, which involves homo- and hetero-oligomerization through their inhibitory C-terminal region.

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

Similar content being viewed by others

References

  • Aghazadeh B, Lowry WE, Huang XY and Rosen MK . (2000). Cell, 102, 625–633.

  • Anborgh PH, Qian X, Papageorge AG, Vass WC, DeClue JE and Lowy DR . (1999). Mol. Cell. Biol., 19, 4611–4622.

  • Aurandt J, Vikis HG, Gutkind JS, Ahn N and Guan KL . (2002). Proc. Natl. Acad. Sci. USA, 99, 12085–12090.

  • Bustelo XR . (2000). Mol. Cell. Biol., 20, 1461–1477.

  • Cerione RA and Zheng Y . (1996). Curr. Opin. Cell Biol., 8, 216–222.

  • Chikumi H, Fukuhara S and Gutkind JS . (2002). J. Biol. Chem., 277, 12463–12473.

  • Crespo P, Schuebel KE, Ostrom AA, Gutkind JS and Bustelo XR . (1997). Nature, 385, 169–172.

  • Fukuhara S, Chikumi H and Gutkind JS . (2000). FEBS Lett., 485, 183–188.

  • Fukuhara S, Chikumi H and Gutkind JS . (2001). Oncogene, 20, 1661–1668.

  • Fukuhara S, Murga C, Zohar M, Igishi T and Gutkind JS . (1999). J. Biol. Chem., 274, 5868–5879.

  • Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA and Broek D . (1998). Science, 279, 558–560.

  • Hart MJ, Eva A, Zangrilli D, Aaronson SA, Evans T, Cerione RA and Zheng Y . (1994). J. Biol. Chem., 269, 62–65.

  • Hart MJ, Jiang X, Kozasa T, Roscoe W, Singer WD, Gilman AG, Sternweis PC and Bollag G . (1998). Science, 280, 2112–2114.

  • Hill CS, Wynne J and Treisman R . (1995). Cell, 81, 1159–1170.

  • Kim S, Lee SH and Park D . (2001). J. Biol. Chem., 276, 10581–10584.

  • Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G and Sternweis PC . (1998). Science, 280, 2109–2111.

  • Lambert JM, Lambert QT, Reuther GW, Malliri A, Siderovski DP, Sondek J, Collard JG and Der CJ . (2002). Nat. Cell Biol., 4, 621–625.

  • Longenecker KL, Lewis ME, Chikumi H, Gutkind JS and Derewenda ZS . (2001). Structure (Camb), 9, 559–569.

  • Nimnual AS, Yatsula BA and Bar-Sagi D . (1998). Science, 279, 560–563.

  • Perrot V, Vazquez-Prado J and Gutkind JS . (2002). J. Biol. Chem., 277, 43115–43120.

  • Ponting CP . (1999). J. Mol. Med., 77, 695–698.

  • Reid T, Furuyashiki T, Ishizaki T, Watanabe G, Watanabe N, Fujisawa K, Morii N, Madaule P and Narumiya S . (1996). J. Biol. Chem., 271, 13556–13560.

  • Ren XD, Kiosses WB and Schwartz MA . (1999). EMBO J., 18, 578–585.

  • Ridley AJ and Hall A . (1992). Cell, 70, 389–399.

  • Russo C, Gao Y, Mancini P, Vanni C, Porotto M, Falasca M, Torrisi MR, Zheng Y and Eva A . (2001). J. Biol. Chem., 276, 19524–19531.

  • Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H and Gutkind JS . (2002). FEBS Lett., 511, 15–20.

  • Schmidt A and Hall A . (2002). Genes Dev., 16, 1587–1609.

  • Shi CS, Sinnarajah S, Cho H, Kozasa T and Kehrl JH . (2000). J. Biol. Chem., 275, 24470–24476.

  • Swiercz JM, Kuner R, Behrens J and Offermanns S . (2002). Neuron, 35, 51–63.

  • Takai Y, Sasaki T and Matozaki T . (2001). Physiol. Rev., 81, 153–208.

  • Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, Nagao K, Kataoka S and Kaibuchi K . (2001). J. Cell Biol., 155, 809–820.

  • Teramoto H, Salem P, Robbins KC, Bustelo XR and Gutkind JS . (1997). J. Biol. Chem., 272, 10751–10755.

  • Whitehead IP, Campbell S, Rossman KL and Der CJ . (1997). Biochim. Biophys. Acta, 1332, F1–F23.

  • Zheng Y . (2001). Trends Biochem. Sci., 26, 724–732.

  • Zhu K, Debreceni B, Bi F and Zheng Y . (2001). Mol. Cell. Biol., 21, 425–437.

  • Zohar M, Teramoto H, Katz BZ, Yamada KM and Gutkind JS . (1998). Oncogene, 17, 991–998.

Download references

Author information

Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892-4340, MD, USA

    Hiroki Chikumi, Ana Barac, Babak Behbahani, Hidemi Teramoto, Yi Zheng & J Silvio Gutkind

  2. Experimental Hematology, Children's Hospital Research Foundation, Cincinnati, 45229, OH, USA

    Yuan Gao

Authors
  1. Hiroki Chikumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Barac
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Babak Behbahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hidemi Teramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yi Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Silvio Gutkind
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Silvio Gutkind.

Additional information

This article is a ‘United States Government Work’ paper as defined by the US Copyright Act

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chikumi, H., Barac, A., Behbahani, B. et al. Homo- and hetero-oligomerization of PDZ-RhoGEF, LARG and p115RhoGEF by their C-terminal region regulates their in vivo Rho GEF activity and transforming potential. Oncogene 23, 233–240 (2004). https://doi.org/10.1038/sj.onc.1207012

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207012

Keywords

This article is cited by

Search

Advanced search

Quick links