Mechanisms of cytosolic targeting of matrix metalloproteinase-2

J Cell Physiol. 2012 Oct;227(10):3397-404. doi: 10.1002/jcp.24040.


Matrix metalloproteinase-2 (MMP-2) is best understood for its biological actions outside the cell. However, MMP-2 also localizes to intracellular compartments and the cytosol where it has several substrates, including troponin I (TnI). Despite a growing list of cytosolic substrates, we currently do not know the mechanism(s) that give rise to the equilibrium between intracellular and secreted MMP-2 moieties. Therefore, we explored how cells achieve the unique distribution of this protease. Our data show that endogenous MMP-2 targets inefficiently to the endoplasmic reticulum (ER) and shows significant amounts in the cytosol. Transfection of canonical MMP-2 essentially reproduces this targeting pattern, suggesting it is the quality of the MMP-2 signal sequence that predominantly determines MMP-2 targeting. However, we also found that human cardiomyocytes express an MMP-2 splice variant which entirely lacks the signal sequence. Like the fraction of ER-excluded, full-length MMP-2, this variant MMP-2 is restricted to the cytosol and specifically enhances TnI cleavage upon hypoxia-reoxygenation injury in cardiomyocytes. Together, our findings describe for the first time a set of mechanisms that cells utilize to equilibrate MMP-2 both in the extracellular milieu and intracellular, cytosolic locations. Our results also suggest approaches to specifically investigate the overlooked intracellular biology of MMP-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia / physiology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cytosol / enzymology
  • Cytosol / metabolism*
  • DNA, Complementary / genetics
  • Endoplasmic Reticulum / enzymology
  • Endoplasmic Reticulum / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Matrix Metalloproteinase 2 / metabolism*
  • Myocytes, Cardiac / enzymology
  • Myocytes, Cardiac / metabolism
  • Transfection / methods
  • Troponin I / metabolism


  • DNA, Complementary
  • Troponin I
  • Matrix Metalloproteinase 2