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Volume 10Nov 2009

Scientific Report

  • EMBO reports advance online publication 6 November 2009; doi:10.1038/embor.2009.233

The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in ApcMin/+mice

Yoshihiro Kawasaki1,*, Shinnosuke Tsuji1,*, Ken Muroya1,2,*, Shiori Furukawa1, Yoko Shibata1, Masumi Okuno1, Susumu Ohwada2 & Tetsu Akiyama1

  1. Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan
  2. Department of Surgery, Gunma University, Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan

Correspondence to:

Tetsu Akiyama, Tel: +81 3 5841 8483; Fax: +81 3 5841 8482;
E-mail: akiyama@iam.u-tokyo.ac.jp

*These authors contributed equally to this work

Received 15 April 2009; Revised 22 September 2009; Accepted 23 September 2009

Sporadic and familial colorectal tumours usually harbour biallelic adenomatous polyposis coli (APC)-associated mutations that result in constitutive activation of Wnt signalling. Furthermore, APC activates Asef and Asef2, which are guanine-nucleotide exchange factors specific for Rac1 and Cdc42. Here, we show that Asef and Asef2 expression is aberrantly enhanced in intestinal adenomas and tumours. We also show that deficiency of either Asef or Asef2 significantly reduces the number and size of adenomas in Apc Min/+ mice, which are heterozygous for an APC mutation and spontaneously develop adenomas in the intestine. We observed that the APC–Asef/Asef2 complex induces c-Jun amino-terminal kinase-mediated transactivation of matrix metalloproteinase 9, and is required for the invasive activity of colorectal tumour cells. Furthermore, we show that Asef and Asef2 are required for tumour angiogenesis. These results suggest that Asef and Asef2 have a crucial role in intestinal adenoma formation and tumour progression, and might be promising molecular targets for the treatement of colorectal tumours.

  • Keywords:

    • APC,
    • Asef,
    • invasion,
    • metalloproteinase,
    • tumour