Processing of Integrin αv Subunit by Membrane Type 1 Matrix Metalloproteinase Stimulates Migration of Breast Carcinoma Cells on Vitronectin and Enhances Tyrosine Phosphorylation of Focal Adhesion Kinase

Elena I Deryugina,Boris I Ratnikov,Tanya I Postnova,Dmitri V Rozanov,Alex Y Strongin

doi:10.1074/jbc.m110269200

Abstract

Recently, we have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. Similar to furin-like proprotein convertases, MT1-MMP directly processes a single chain precursor of alpha(v) integrin subunit (pro-alpha(v)) into the heavy and light alpha-chains connected by a disulfide bridge. To evaluate functionality of MT1-MMP-processed integrins, we examined breast carcinoma MCF7 cells co-expressing alpha(v)beta(3) integrin with either the wild type or mutant MT1-MMP in a variety of migration and adhesion tests. Specific inhibitors of proprotein convertases and MMP were employed in our cell system to attenuate the individual pathways of pro-alpha(v) maturation. We present evidence that MT1-MMP cleavage of pro-alpha(v) in the cells did not affect RGD-ligand binding of the resulting alpha(v)beta(3) integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and alpha(v)beta(3) integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of alpha(v)beta(3) integrin. These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and alpha(v)beta(3) integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. Regulation of integrin maturation and functionality may be an important role of MT1-MMP in tumor cells.

Highlights

We have shown that membrane type 1 matrix metalloproteinase (MT1-matrix metalloproteinases (MMPs)) exhibits integrin convertase activity
Individually or jointly, failed to modulate significantly migration of ␤3/zeo cells (Fig. 6). These results suggest that ␣v␤3 integrin processed by membrane type 1 matrix metalloproteinase (MT1-MMP) is likely to be more efficient in vitronectin-mediated cell migration relative to the integrin processed by the conventional furin-like proprotein convertases
Emerging evidence indicates that membrane-tethered MMPs such as MT1-MMP are directly involved in endoproteolytic modifications of cell surface receptors including CD44, tissue transglutaminase, and ␣v␤3 integrin [20, 21, 35, 36]

Summary

Introduction

We have shown that membrane type 1 matrix metalloproteinase (MT1-MMP) exhibits integrin convertase activity. We present evidence that MT1-MMP cleavage of pro-␣v in the cells did not affect RGD-ligand binding of the resulting ␣v␤3 integrin but enhanced outside-in signal transduction through a focal adhesion kinase pathway. Enhanced tyrosine phosphorylation of focal adhesion kinase in cells co-expressing MT1-MMP and ␣v␤3 integrin contributed to efficient adhesion and, especially, migration of cells on vitronectin, a ligand of ␣v␤3 integrin These mechanisms underscore the significance of a coordinated interplay between MT1-MMP and ␣v␤3 integrin in tumor cells and identify downstream signaling pathways resulting from their interactions. The cleavage at the highly conserved pairs of basic amino acids is known to be a function of furin-like proprotein convertases from the subtilisin/kexin family This cleavage converts a single ␣-chain precursor into the mature subunit consisting of an N-terminal heavy ␣-chain and a C-terminal light ␣-chain connected by a disulfide bridge [16]. There is a strong correlation between the expression of MT1-MMP and tumorigenesis in many cancer types [33, 37, 38]

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Conclusion