Alpha1,6-fucosyltransferase (
Fut8) plays important roles inphysiological and pathological conditions.
Fut8-deficient (
Fut8/)mice exhibit growth retardation, earlier postnatal death, andemphysema-like phenotype. To investigate the underlying molecularmechanism by which growth retardation occurs, we examined themRNA expression levels of
Fut8/ embryos (18.5days postcoitum [dpc]) using a cDNA microarray. The DNA microarrayand real-time polymerase chain reaction (PCR) analysis showedthat a group of genes, including trypsinogens 4, 7, 8, 11, 16,and 20, were down-regulated in
Fut8/ embryos.Consistently, the expression of trypsinogen proteins was foundto be lower in
Fut8/ mice in the duodenum, smallintestine, and pancreas. Trypsin, an active form of trypsinogen,regulates cell growth through a G-protein-coupled receptor,the proteinase-activated receptor 2 (PAR-2). In a cell culturesystem, a
Fut8 knockdown mouse pancreatic acinar cell carcinoma,TGP49-
Fut8-KDs, showed decreased growth rate, similar to thatseen in
Fut8/ mice, and the decreased growth ratewas rescued by the application of the PAR-2-activating peptide(SLIGRL-NH
2). Moreover, epidermal growth factor (EGF)-inducedreceptor phosphorylation was attenuated in TGP49-
Fut8-KDs, whichwas highly associated with a reduction of trypsinogens mRNAlevels. The addition of exogenous EGF recovered c-fos, c-jun,and trypsinogen mRNA expression in TGP49-
Fut8-KDs. Again, theEGF-induced up-regulation of c-fos and c-jun mRNA expressionwas significantly blocked by the protein kinase C (PKC) inhibitor.Our findings clearly demonstrate a relationship between
Fut8and the regulation of EGF receptor (EGFR)-trypsin-PAR-2 pathwayin controlling cell growth and that the EGFR-trypsin-PAR-2 pathwayis suppressed in TGP49-
Fut8-KDs as well as in
Fut8/mice.
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