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 Article
  • Published:

Identification and characterization of Asef2, a guanine–nucleotide exchange factor specific for Rac1 and Cdc42

Oncogene volume 26, pages 7620–7627 (2007)Cite this article

Abstract

The tumor suppressor adenomatous polyposis coli (APC) is mutated in sporadic and familial colorectal tumors. APC interacts with the Rac1-specific guanine–nucleotide exchange factor (GEF) Asef, which contains an APC-binding region (ABR) in addition to Dbl homology (DH), Pleckstrin (PH) and Src homology 3 (SH3) domains. APC stimulates the GEF activity of Asef, and thereby regulates cell adhesion and migration. Here, we have identified a second Asef, termed Asef2, that shows significant structural and functional similarities to Asef. We found that both the N-terminal ABR and SH3 domains of Asef2 are responsible for its interaction with APC. When expressed in HeLa cells, a mutant Asef2 lacking the ABR and SH3 domains, Asef2-ΔABR/SH3, induced increases in the levels of the active forms of Rac1 and Cdc42. Full-length Asef2 also showed this activity when co-transfected with truncated mutant APC expressed in colorectal tumor cells. Consistent with this, either Asef2-ΔABR/SH3 or Asef2 plus truncated mutant APC stimulated lamellipodia formation in MDCK cells and filopodia formation in HeLa cells. Furthermore, RNA interference experiments showed that Asef2 is required for migration of colorectal tumor cells expressing truncated APC. These results suggest that similar to Asef, Asef2 plays an important role in cell migration, and that Asef2 activated by truncated mutant APC is required for aberrant migration of colorectal tumor cells.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Akiyama T, Kawasaki Y . (2006). Wnt signaling and the actin cytoskeleton. Oncogene 25: 7538–7544.

    Article  CAS  Google Scholar 

  • Bienz M, Clevers H . (2000). Linking colorectal cancer to Wnt signaling. Cell 103: 311–320.

    Article  CAS  Google Scholar 

  • Cadigan KM, Nusse R . (1997). Wnt signaling: a common theme in animal development. Genes Dev 11: 3286–3305.

    Article  CAS  Google Scholar 

  • Feng Q, Baird D, Cerione RA . (2004). Novel regulatory mechanisms for the Dbl family guanine nucleotide exchange factor Cool-2/a-Pix. EMBO J 23: 3492–3504.

    Article  CAS  Google Scholar 

  • Fodde R, Smits R, Clevers H . (2001). APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer 1: 55–67.

    Article  CAS  Google Scholar 

  • Gotthardt K, Ahmadian MR . (2007). Asef is a Cdc-42-specific guanine nucleotide exchange factor. Biol Chem 388: 67–71.

    Article  CAS  Google Scholar 

  • Hall A . (1998). Rho GTPases and the actin cytoskeleton. Science 279: 509–514.

    Article  CAS  Google Scholar 

  • Hamann MJ, Lubking CM, Luchini DN, Billadeau DD . (2007). Asef2 functions as a Cdc42 exchange factor and is stimulated by the release of an autoinhibitory module from a concealed C-terminal activation element. Mol Cell Biol 27: 1380–1393.

    Article  CAS  Google Scholar 

  • Jimbo T, Kawasaki Y, Koyama R, Sato R, Takada S, Haraguchi K et al. (2002). Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nat Cell Biol 4: 323–327.

    Article  CAS  Google Scholar 

  • Kawasaki Y, Sato R, Akiyama T . (2003). Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nat Cell Biol 5: 211–215.

    Article  CAS  Google Scholar 

  • Kawasaki Y, Senda T, Ishidate T, Koyama R, Morishita T, Iwayama Y et al. (2000). Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289: 1194–1197.

    Article  CAS  Google Scholar 

  • Kinzler KW, Vogelstein B . (1996). Lessons from hereditary colorectal cancer. Cell 87: 159–170.

    Article  CAS  Google Scholar 

  • Matsumine A, Ogai A, Senda T, Okumura N, Satoh K, Baeg G-H et al. (1996). Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science 272: 1020–1023.

    Article  CAS  Google Scholar 

  • Murayama K, Shirouzu M, Kawasaki Y, Kato-Murayama M, Hanawa-Suetsugu K, Sakamoto A et al. (2007). Crystal structure of the rac activator, Asef, reveals its autoinhibitory mechanism. J Biol Chem 282: 4238–4242.

    Article  CAS  Google Scholar 

  • Oshima H, Oshima M, Kobayashi M, Tsutsumi M, Taketo MM . (1997). Morphological and molecular processes of polyp formation in Apc (delta716) knockout mice. Cancer Res 57: 1644–1649.

    CAS  Google Scholar 

  • Polakis P . (2000). Wnt signaling and Cancer. Genes Dev 14: 1837–1851.

    CAS  Google Scholar 

  • Sansom OJ, Reed KR, Hayes AJ, Ireland H, Brinkmann H, Newton IP et al. (2004). Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. Genes Dev 18: 1385–1390.

    Article  CAS  Google Scholar 

  • Van Aelst L, D'Souza-Schorey C . (1997). Rho GTPases and signaling networks. Genes Dev 11: 2295–2322.

    Article  CAS  Google Scholar 

  • Watanabe T, Wang S, Noritake J, Sato K, Fukuta M, Takefuji M et al. (2005). Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell 7: 871–883.

    Article  Google Scholar 

  • Wong MH, Hermiston ML, Syder AJ, Gordon JI . (1996). Forced expression of the tumor suppressor adenomatous polyposis coli protein induces disordered cell migration in the intestinal epithelium. Proc Natl Acad Sci USA 93: 9588–9593.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y Nabeshima for GST-PAK CRIB, A Blangy for GST-RhoGIP122 and Y Takai for Dbl-ΔN.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

    Y Kawasaki, M Sagara, Y Shibata & T Akiyama

  2. RIKEN Genomic Sciences Center, Yokohama Institute, Kanagawa, Bunkyo-ku, Tokyo, Japan

    M Shirouzu & S Yokoyama

  3. Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Tokyo, Japan

    S Yokoyama

Authors
  1. Y Kawasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Sagara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Shibata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Shirouzu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Akiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawasaki, Y., Sagara, M., Shibata, Y. et al. Identification and characterization of Asef2, a guanine–nucleotide exchange factor specific for Rac1 and Cdc42. Oncogene 26, 7620–7627 (2007). https://doi.org/10.1038/sj.onc.1210574

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210574

Keywords

This article is cited by

Search

Advanced search

Quick links