The K-sam gene was originally cloned from KATO-III human gastric cancer cells and is identical to the bek or keratinocyte growth factor (KGF) receptor (KGFR) or fibroblast growth factor receptor 2 gene. K-sam generates several variant transcripts by alternative splicing, and the most abundant K-sam transcript in KATO-III cells was cloned as the K-sam-IIC3 cDNA, which has the KGF-binding motif and a short carboxyl terminus lacking a putative phospholipase C-gamma 1 association site, Tyr-769. The K-sam-IIC3 cDNA was distinct from the K-sam-IIC1 cDNA, which was the same as the previously reported KGFR cDNA. The K-sam-IIC1 product contains a long carboxyl terminus with Tyr-769. K-sam-IIC3 showed greater transforming activity in NIH 3T3 cells than did K-sam-IIC1, and in gastric cancer cell lines in general, the level of K-sam-IIC3 mRNA was greater than that of K-sam-IIC1 mRNA. Here we report that the K-sam-IIC3 product was less autophosphorylated than the K-sam-IIC1 product in NIH 3T3 transfectants. K-sam-IIC3-transfected keratinocytes showed a stronger mitogenic response to KGF than did K-sam-IIC1 transfectants. Moreover, K-sam-IIC3-transfected L6 myoblast cells hardly differentiated when cultured in differentiation-inducing medium and growth was not significantly affected, while K-sam-IIC1 transfectants showed a differentiated phenotype with a reduced growth rate. These data indicate the difference in the signal transduction mediated by two KGFR-type K-sam variants generated by alternative splicing which might be involved in certain differentiation and carcinogenesis scenarios.