Cellular membrane type-1 matrix metalloproteinase (MT1-MMP) cleaves C3b, an essential component of the complement system

J Biol Chem. 2004 Nov 5;279(45):46551-7. doi: 10.1074/jbc.M405284200. Epub 2004 Sep 14.

Abstract

Neoplasms have developed numerous strategies to protect themselves against the host immune system. Membrane type-1 matrix metalloproteinase (MT1-MMP) is strongly associated with many cancer types and is up-regulated in the aggressive, metastatic neoplasms. During the past few years, there has been an increasing appreciation of the important, albeit incompletely understood, role of MT1-MMP in cancer. We have discovered, using cell-free and cell-based assays in vitro, that MT1-MMP proteolysis specifically targets C3b, an essential component of the complement propagation pathway. MT1-MMP proteolysis liberates the deposited C3 activation fragments from the cell surface. The shedding of these cell-deposited opsonins by MT1-MMP inhibits the complement cascade and protects breast carcinoma MCF7 cells from direct complement-mediated injury in the in vitro tests. The functional link associating MT1-MMP with the host immune system, heretofore unrecognized, may empower tumors with an escape mechanism that contributes to the protection against the host anti-tumor immunity as well as to the survival of invading and metastatic malignant cells in the bloodstream.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Separation
  • Cell-Free System
  • Complement C3b / metabolism*
  • Complement C4b / metabolism
  • Complement System Proteins / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / metabolism
  • Metalloendopeptidases / physiology*
  • Opsonin Proteins / metabolism
  • Protein Binding
  • Time Factors
  • Transfection

Substances

  • Opsonin Proteins
  • Complement C3b
  • Complement C4b
  • Complement System Proteins
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2