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J. Biol. Chem., Vol. 279, Issue 25, 26533-26539, June 18, 2004

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The Integrin Cytoplasmic-tail Motif EKQKVDLSTDC Is Sufficient to Promote Tumor Cell Invasion Mediated by Matrix Metalloproteinase (MMP)-2 or MMP-9^*

Mark R. Morgan, Gareth J. Thomas, Alan Russell¶, Ian R. Hart, and John F. Marshall||

From the Tumour Biology Laboratory, Cancer Research UK Clinical Centre, Barts and The London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Sq., London EC1M 6BQ, United Kingdom, Eastman Dental Institute, 256 Grays Inn Road, London WC1X 8LD, United Kingdom, and ^¶Department of Dermatology, Stanford University Medical Center, Palo Alto, California 94305-5486

Integrins promote cellular invasion through a combination of activities, including adhesion to an extracellular matrix ligand, which result in the generation of intracellular signals that lead to changes in cell behavior. Until now, there have been no data that identify a particular region of the cytoplasmic tail of integrin subunits as being responsible specifically for promoting the invasive activity of tumor cells. In this report, we show that amino acids with the sequence EKQKVDLSTDC, which are the C-terminal residues of the integrin 6 subunit, promote v6-dependent invasion in a matrix metalloproteinase (MMP)-9-dependent fashion. This same peptide sequence, when expressed at the cytoplasmic end of the 3 integrin subunit, was able to enhance v3-mediated invasive and enzymatic activity of tumor cells in an MMP-2-dependent fashion. Our results show that these 11 amino acids, when expressed at the C terminus of the subunit, are responsible for regulating the activity of invasion-promoting degradative enzymes, whereas the specific MMP involved in this cellular behavior is dependent on the context of the remainder of the integrin subunit.

Received for publication, February 17, 2004 , and in revised form, March 31, 2004.

^* 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 should be addressed. Tel.: 44-20-7014-0400; Fax: 44-20-7014-0401; E-mail: john.marshall{at}cancer.org.uk.

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