Dysregulated cell motility is one of the major characteristics of invasion and metastatic potentials of malignant
tumor cells. Here, we examined the
hepatocyte growth factor (HGF)-induced cell motility of two human
renal carcinoma cell lines, ACHN and VMRC-RCW. Scattering and migration was induced in ACHN in an HGF-dependent manner, whereas they were maintained in VMRC-RCW even in the absence of HGF. In VMRC-RCW,
HGF receptor (HGFR)
tyrosine kinase was constitutively active, and sequence analysis showed N375S, A1209G and V1290L mutations. However, transfection experiments using porcine aortic endothelial (PAE) cells demonstrated that no single mutation or combination of two or three mutations caused HGF-independent constitutive activation. Conversely, the expressed amount of receptor
protein had a pivotal role in the basal
kinase activity. With respect to downstream signaling molecules of HGFR in ACHN or VMRC-RCW, the Ras-MAPK pathway was downregulated, whereas
phosphoinositide 3-kinase (PI3-kinase) was not further activated by HGF-treatment in VMRC-RCW cells. The
PI3-kinase inhibitors,
wortmannin and
LY294002 strongly inhibited spontaneous migration of VMRC-RCW. One transfected PAE cell line with massive overexpression of HGFR demonstrated scattered morphology and increased
PI3-kinase activity in association with increased motility, which was partially inhibited by
LY294002. Taken together, our results indicate that the overexpression of HGFR causes increase in cellular motility and
PI3-kinase shows the important contribution on the increased motility of
renal carcinoma cells.