The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in Apc(Min/+)mice.
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 treatment of colorectal tumours.
Kawasaki
Yoshihiro
Y
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.
Tsuji
Shinnosuke
S
Muroya
Ken
K
Furukawa
Shiori
S
Shibata
Yoko
Y
Okuno
Masumi
M
Ohwada
Susumu
S
Akiyama
Tetsu
T
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D017491:Genes, APC / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D045325:HCT116 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
C576602:ARHGEF4 protein, human; C547838:Arhgef4 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C547839:Spata13 protein, mouse; D020780:Matrix Metalloproteinase 9