A Mechanism for Regulation of Melanoma Invasion. LIGATION OF alpha 6beta 1 INTEGRIN BY LAMININ G PEPTIDES

doi:10.1074/jbc.271.44.27221

Volume 271, Number 44, Issue of November 1, 1996 pp. 27221-27224
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

A Mechanism for Regulation of Melanoma Invasion
LIGATION OF $alpha$ ₆ $beta$ ₁ INTEGRIN BY LAMININ G PEPTIDES

(Received for publication, July 1, 1996, and in revised form, August 19, 1996)

Hirokazu Nakahara , Motoyoshi Nomizu ^§ , Steven K. Akiyama ^§ , Yoshihiko Yamada ^§ , Yunyun Yeh and Wen-Tien Chen

From the Lombardi Cancer Center and Department of Cell Biology, Georgetown University Medical Center, Washington, D. C. 20007 and the ^§ Laboratory of Developmental Biology, NIDR, National Institutes of Health, Bethesda, Maryland 20892

Invasion of LOX human melanoma cells involves extracellular matrix (ECM) degradation and formation of cell surface invadopodia. Here we show that the ligation of $alpha$ ₆ $beta$ ₁ by two peptides derived from the COOH-terminal globular domain of laminin-1 $alpha$ ₁ chain (laminin G peptides), designated AG-10 (NPWHSIYITRFG) and AG-32 (TWYKIAFQRNRK), and antibodies against $alpha$ ₆ and $beta$ ₁ integrins promoted invasiveness. AG-10 and AG-32 inhibited cell adhesion on laminin, and the antibodies blocked cell adhesion on immobilized AG-10 and AG-32, suggesting that the peptides interact primarily with $alpha$ ₆ $beta$ ₁ integrin. These soluble peptides and integrin antibodies induced invasiveness by causing an 2-3-fold increase in ECM degradation and invadopodial activity independently of adhesion activity of integrins that were prebound to ECM. The induced ECM degradation and invasion was associated with an increased surface expression of the 170-kDa membrane-bound gelatinase, seprase, as well as its intense localization at invadopodia but not at focal adhesions. However, the total expression levels of seprase, gelatinase A and $beta$ ₁ integrins were not altered. We suggest that laminin G peptides act on the $alpha$ ₆ $beta$ ₁ integrin signaling of invasion by stimulating invadopodial activities, which is distinct from their direct effects on cell adhesion on immobilized ECM.

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