ENHANCED MODULATION OF KERATINOCYTE MOTILITY BY TRANSFORMING GROWTH-FACTOR-ALPHA (TGF-ALPHA) RELATIVE TO EPIDERMAL GROWTH-FACTOR (EGF)

Epidermal growth factor (EGF) and transforming growth factor (TGF)-alp ha are high-affinity polypeptide ligands for the EGF receptor, which m ediates their biologic activities. In this study, we directly compared the actions of both ligands in promoting keratinocyte motility. We fo und that normal and tumorigenic human keratinocytes responded to activ ation of the EGF receptor by either EGF or TGF-alpha; however, the two ligands did not elicit identical responses with regard to cell locomo tion. TGF-alpha was more effective than EGF at promoting colony disper sion (cell scattering), in vitro wound closure, and single-cell migrat ion as assessed by phagokinetic track analysis, In contrast, EGF and T GF-alpha evoked identical profiles for DNA synthesis with regard to co ncentration dependence and magnitude of response in normal keratinocyt es and in a squamous cell carcinoma line. The overall pattern of tyros ine phosphorylation of intracellular substrates was similar when cells were stimulated with either growth factor; however, a limited number of differences in the kinetics or magnitude of protein phosphorylation were detected in subcellular fractions. These findings demonstrate th at two growth factors implicated in promoting mitogenesis and locomoti on may elicit divergent responses with regard to one biologic activity while retaining similar responses for other activities. This suggests that ligand-mediated mitogenic responses may not be tightly coupled t o motogenic activity and further illustrates the multifunctional roles of polypeptide growth factors.