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

• Published in: EMBO reports 2009-12, Vol.10 (12), p.1355-1362
• Main Authors: Akiyama, Tetsu, Kawasaki, Yoshihiro, Tsuji, Shinnosuke, Muroya, Ken, Furukawa, Shiori, Shibata, Yoko, Okuno, Masumi, Ohwada, Susumu
• Format: Article
• Language: English
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2009.233

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. Kawasaki and colleagues show that the APC‐associated guanine nucleotide exchange factors Asef and Asef2 induce JNK‐mediated transactivation of metalloproteinase (MMP)‐9 and are required for intestinal adenoma formation and tumor progression. These findings suggest that Asef and Asef2 may be promising molecular targets for therapy of colorectal tumors.