Glycobiology Advance Access published online on March 29, 2006
Glycobiology, doi:10.1093/glycob/cwj108
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1 Division of Gastroenterology, School of Clinical Science, Nuffield Building, Crown Street, University of Liverpool, Liverpool, L69 3BX, UK
* To whom correspondence should be addressed. Peanut lectin (PNA) binds the Thomsen-Friedenreich (TF) oncofetal carbohydrate antigen (galactose
Received October 28, 2005
Revised March 17, 2006
Accepted March 23, 2006
Article
Peanut lectin stimulates proliferation of colon cancer cells by interaction with glycosylated CD44v6 isoforms and consequential activation of c-Met and MAPK: Functional implications for disease-associated glycosylation changes
Ravinder Singh 1,
Sreedhar Subramanian 1,
Jonathan M. Rhodes 1,
and
Barry J. Campbell 1 *
Barry J. Campbell, E-mail: bjcampbl{at}liv.ac.uk
Abstract 
1-3N-acetylgalactosamine
-) that shows increased expression in colon cancer, adenomas and inflammatory bowel disease. PNA is mitogenic, both in vitro and in vivo, for colon epithelial cells. In these cells, PNA binds predominantly to cell-surface TF antigen expressed by high molecular weight isoforms of the transmembrane glycoprotein CD44 that are generated in inflamed and neoplastic colonic epithelia by altered RNA splicing. Our aim was to identify the signalling mechanism underlying the proliferative response to PNA. This was investigated in HT29, T84 and Caco2 colon cancer cells. Parallel lectin and immuno-blotting of PNA affinity-purified HT29 cell membrane extracts showed PNA binding to high molecular weight CD44v6 isoforms. Within 5 min, PNA (25µg/ml) caused a 6-fold increase in phosphorylation of hepatocyte growth factor receptor c-Met, known to co-associate with CD44v6. This was followed by downstream activation of p44/p42 MAPK over 15-20 min. The presence of 100µg/ml asialofetuin, a TF antigen-expressing glycoprotein, blocked both PNA-induced c-Met and MAPK activation. A similar PNA-induced c-Met and MAPK phosphorylation was also seen in T84 cells, which express CD44v6 but not in Caco2 cells, which lack CD44v6. PNA-induced cell proliferation was completely blocked by 1µM PD98059, an inhibitor of MAPK activation (p<0.0001). The expression of TF antigen by CD44 isoforms in colonic epithelial cells allows lectin-induced mitogenesis that is mediated by phosphorylation of c-Met and MAPK. It provides a mechanism by which dietary, microbial or endogenous galactose-binding lectins could affect epithelial proliferation in the cancerous and pre-cancerous colon.
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