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J. Biol. Chem., Vol. 278, Issue 22, 19861-19869, May 30, 2003

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Integrin ₂ and Extracellular Signal-regulated Kinase Are Functionally Linked in Highly Malignant Autocrine Transforming Growth Factor--driven Colon Cancer Cells^*

Rajinder S. Sawhney , Bhavya Sharma, Lisa E. Humphrey and Michael G. Brattain 

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Recently, we have shown that autocrine transforming growth factor- (TGF-) controls the expression of integrin ₂, 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 ₂ 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 ₂ expression, cell adhesion, and activation of ERK are inhibited in a parallel concentration-dependent fashion. Moreover, autocrine TGF--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- 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 ₂-mediated cell micromotion signaling is controlled by autocrine TGF-. Thus, this study implicates ERK/MAPK signaling activated by endogenous TGF- as one of the mechanistic features controlling metastatic spread.

Received for publication, December 26, 2002 , and in revised form, March 19, 2003.

^* This work was supported in part by National Institutes of Health Grants CA 54807, 34432, and 50457 and by the Shelby Rae Tengg Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: rajinder.sawhney{at}roswellpark.org. To whom correspondence may be addressed. Dept. of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-3044; Fax: 716-845-8857; E-mail: michael.brattain{at}roswellpark.org.

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