Differentiation of Pancreatic Endocrine Cells

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1) We established a model cell system to study the differentiation of pancreatic endocrine cells.2) Using this sytem, we found that activin A and betacellulin (BTC) convert amylase secreting cells into insulin-secreting cells.3) We also found that hepatocyte growth factor (HGF) reproduce the effect of BTC.4) In AR42J cells, there specific binding sites to BTC.The binding of BTC is replaced by unlabeled BTC but EGF is much less potent. BTC binds to ErbB1 and another protein of MW of 190 KDa, which may be a new member of the EGF receptor family. BTC induced tyrosine phosphorylation of ErbB1, ErbB2, ErbB4 and the 190 KDa protein.5) The differentiation-inducing activity is blocked by an inhibitor of the MAP knase pathway but not by an inhibitor of the Pl 3-kinase pathway. In addition, transfection of Ar42J cells with cDNA for constitutively active MAP kinase kinase induced differentiation. Conversely, transfection of cDNA for MAP inase phosphatase blocked differentiation. Activation of MAP kinase is neccesry and sufficient for the HGF-induced differentiation of AR42J cells.6) We examine the genes expressed during the differentiation of AR42J cells inot insulin-producing cells by differential display. Activin A and BTC induced the expression of 25 genes, 10 of which are unique ones. Expression of some of them was blocked by an inhibitor of MAP kinase. Therefore, these genes are cloosely associated with differentiation of AR42J cells.