Integrin α₂ and extracellular signal-regulated kinase are functionally linked in highly malignant autocrine transforming growth factor-α-driven colon cancer cells

Recently, we have shown that autocrine transforming growth factor-α (TGF-α) controls the expression of integrin α₂, cell adhesion to collagen IV and motility in highly progressed HCT116 colon cancer cells (Sawhney, R. S., Zhou, G-H. K., Humphrey, L. E., Ghosh, P., Kreisberg, J. I., and Brattain, M. G. (2002) J. Biol. Chem. 277, 75-86). We now report that expression of basal integrin α₂ and its biological effects are controlled by constitutive activation of the extracellular signal-regulated/mitogen-activated protein kinase (ERK/MAPK) pathway. Treatment of cells with selective mitogena-ctivated protein kinase kinase (MEK) inhibitors PD098059 and U0126 showed that integrin α₂ expression, cell adhesion, and activation of ERK are inhibited in a parallel concentration-dependent fashion. Moreover, autocrine TGF-α-mediated epidermal growth factor receptor activation was shown to control the constitutive activation of the ERK/MAPK pathway, since neutralizing antibody to the epidermal growth factor receptor was able to block basal ERK activity. TGF-α antisense-transfected cells also showed attenuated activation of ERK. Using a real time electric cell impedance sensing technique, it was shown that ERK-dependent integrin α₂-mediated cell micromotion signaling is controlled by autocrine TGF-α. Thus, this study implicates ERK/MAPK signaling activated by endogenous TGF-α as one of the mechanistic features controlling metastatic spread.