An Alternative Processing of Integrin αv Subunit in Tumor Cells by Membrane Type-1 Matrix Metalloproteinase

Jeffrey W. Smith,Tanya I. Postnova,Galina G. Chestukhina,Peter G. Baciu,Heying Zhang,Alex Y. Strongin,Richard G. DiScipio,Boris I. Ratnikov,Elena I. Deryugina,Dmitri V. Rozanov

doi:10.1074/jbc.m109580200

Jeffrey W. Smith, Tanya I. Postnova + Show 8 more

Open Access

https://doi.org/10.1074/jbc.m109580200

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Journal: Journal of Biological Chemistry	Publication Date: Mar 1, 2002
Citations: 156	License type: cc-by

Abstract

Membrane type-1 matrix metalloproteinase (MT1-MMP) and alpha(v)beta(3) integrin are both essential to cell invasion. Maturation of integrin pro-alpha(v)chain (pro-alpha(v)) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light alpha chains. Our report presents evidence of an alternative pathway of pro-alpha(v) processing involving MT1-MMP. In breast carcinoma MCF7 cells deficient in MT1-MMP, pro-alpha(v) is processed by a conventional furin-like PC, and the mature alpha(v) integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp(891). In contrast, in cells co-expressing alpha(v)beta(3) and MT1-MMP, MT1-MMP functions as an integrin convertase. MT1-MMP specifically cleaves pro-alpha(v), generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu(892). PC-cleavable alpha(3) and alpha(5) but not the PC-resistant alpha(2) integrin subunit are also susceptible to MT1-MMP cleavage. These novel mechanisms involved in the processing of integrin alpha subunits underscore the significance and complexity of interactions between MT1-MMP and adhesion receptors and suggest that regulation of integrin functionality may be an important role of MT1-MMP in migrating tumor cells.

Highlights

Membrane type-1 matrix metalloproteinase (MT1MMP) and ␣v␤3 integrin are both essential to cell invasion
In breast carcinoma MCF7 cells deficient in MT1MMP, pro-␣v is processed by a conventional furin-like proprotein convertases (PC), and the mature ␣v integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp891
MT1-matrix metalloproteinases (MMPs) cleaves pro-␣v, generating a 115-kDa heavy chain with the truncated C terminus and a 25-kDa light chain commencing from the N-terminal Leu892

Summary

Introduction

Membrane type-1 matrix metalloproteinase (MT1MMP) and ␣v␤3 integrin are both essential to cell invasion. Maturation of integrin pro-␣v chain (pro-␣v) involves its cleavage by proprotein convertases (PC) to form the disulfide-bonded 125-kDa heavy and 25-kDa light ␣ chains. In breast carcinoma MCF7 cells deficient in MT1MMP, pro-␣v is processed by a conventional furin-like PC, and the mature ␣v integrin subunit is represented by the 125-kDa heavy chain and the 25-kDa light chain commencing from the N-terminal Asp891. A member of the PC family, has been implicated in the cleavage of pro-␣5, -␣6, and -␣v chains [7, 8] The role of this cleavage in integrin function is unclear. Expression of integrin ␣v␤3 was repeatedly linked to the activation of MMP-2 in multiple tumor cell types [25,26,27]. In human glioma U251 and melanoma BML cells, ␣v␤3 was shown to co-localize and interact with MT1-MMP [16, 27]

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