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The adenomatous polyposis coli‐associated exchange factors Asef and Asef2 are required for adenoma formation in Apc Min/+ mice
Author(s) -
Kawasaki Yoshihiro,
Tsuji Shinnosuke,
Muroya Ken,
Furukawa Shiori,
Shibata Yoko,
Okuno Masumi,
Ohwada Susumu,
Akiyama Tetsu
Publication year - 2009
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2009.233
Subject(s) - adenomatous polyposis coli , familial adenomatous polyposis , beta catenin , cancer research , wnt signaling pathway , biology , angiogenesis , mutation , adenoma , colorectal cancer , rac1 , cancer , microbiology and biotechnology , signal transduction , genetics , gene
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.