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 mitogen-activated 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.