The majority of deaths from colorectal cancer are due to tumor invasion and metastasis. Induced migration of tumor cell is generally considered to be one critical step in cancer progression to the invasive and metastatic stage. Phospholipase Cgamma1 (PLCgamma1) is a key molecular switch in the process. But, the mechanism and function of PLCgamma1 in colorectal cancer motility are unclear. We showed first in this report that epidermal growth factor (EGF) stimulated the phosphorylation of PLCgamma1 in human colorectal cancer cell line LoVo. Inhibition of PLCgamma1 with the pharmacologic agent U73122 decreased the migration of LoVo cells in a dose-dependent manner while EGF treatment reversed it partially. PLCgamma1 signaling pathway also upregulated the activity of NF-kappaB. Furthermore, expression of Hsp70 was increased by treatment with U73122 or pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor. These data indicated that PLCgamma1 played a pivotal role in the migration of human colorectal cancer cell and first demonstrated that upregulation of NF-kappaB binding activity and downregulation of Hsp70 expression were PLCgamma1-dependent in LoVo cells.