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Mechanisms of cytosolic targeting of matrix metalloproteinase-2

Mohammad A M Ali1, Ava K Chow, Arulmozhi D Kandasamy

  • 1Department of Pharmacology, Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.

Journal of Cellular Physiology
|January 4, 2012
PubMed

Insights

Researchers investigated how Matrix metalloproteinase-2 (MMP-2) distributes inside and outside cells. They found signal sequences and splice variants control MMP-2 localization, impacting troponin I cleavage during cardiac stress.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Matrix metalloproteinase-2 (MMP-2) is primarily known for its extracellular functions.
  • MMP-2 also localizes to intracellular compartments, including the cytosol, where it cleaves substrates like troponin I (TnI).
  • Mechanisms governing the intracellular and extracellular distribution of MMP-2 remain unclear.

Purpose of the Study:

  • To elucidate the mechanisms controlling the unique intracellular and extracellular distribution of MMP-2.
  • To investigate the role of the MMP-2 signal sequence and splice variants in protein targeting.
  • To understand MMP-2's contribution to TnI cleavage in cardiomyocytes.

Main Methods:

  • Analysis of endogenous MMP-2 localization in cells.
  • Transfection studies using canonical MMP-2.
  • Identification and characterization of MMP-2 splice variants in human cardiomyocytes.
  • Assessment of TnI cleavage under hypoxia-reoxygenation conditions.

Main Results:

  • Endogenous MMP-2 exhibits inefficient targeting to the endoplasmic reticulum (ER), with significant cytosolic presence.
  • The MMP-2 signal sequence quality primarily dictates its cellular targeting.
  • A novel MMP-2 splice variant lacking a signal sequence was identified in human cardiomyocytes.
  • This variant, along with ER-excluded full-length MMP-2, accumulates in the cytosol and enhances TnI cleavage during hypoxia-reoxygenation.

Conclusions:

  • Cells utilize distinct mechanisms, including signal sequence efficiency and splice variants, to regulate MMP-2 distribution.
  • An MMP-2 splice variant lacking a signal sequence is restricted to the cytosol.
  • These findings provide insights into the overlooked intracellular biology of MMP-2 and its role in cardiac injury.

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