Nuclear matrix metalloproteinases: functions resemble the evolution from the intracellular to the extracellular compartment

Abstract

Matrix metalloproteinase (MMP) is defined as an endopeptidase in the extracellular matrix (ECM), which plays essential roles in physiological processes such as organogenesis, wound healing, angiogenesis, apoptosis and motility. MMPs are produced and assembled in the cytoplasm as proenzymes with a cytoplasmic domain and require extracellular activation. MMPs can degrade receptors, extracellular matrix proteins, PARPs and release apoptotic substances. MMPs have been found in the cytosol, organelles and extracellular compartments and recently many types of MMPs have been found in the nucleus. However, the mechanisms and roles of MMPs inside the cell nucleus are still poorly understood. Here we summarized the nuclear localization mechanisms of MMPs and their functions in the nucleus such as apoptosis, tissue remodeling upon injury and cancer progression. Most importantly, we found that nuclear MMPs have evolved to translocate to membrane and target ECM possibly through evolution of nuclear localization signal (NLS), natural selection and anti-apoptotic survival. Thus, the knowledge about the evolution and regulation of nuclear MMPs appears to be essential in understanding a variety of cellular processes along with the development of MMP-targeted therapeutic drugs against the progression of certain diseases.

Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP‐2 and BACE‐1 activities, and the modulation of APP trafficking

“…This is conceivable because MT1-MMP harbors a putative nuclear localization sequence that may target the proteinase into the nucleus (23). Moreover, it has been suggested that MT1-MMP nuclear localization carries associated transcription-promoting activity (37). Accordingly, we evaluated by qPCR the mRNA levels (Table 2) for mt1-mmp, mmp-2, mmp-9, and, for App, bace-1 and the members of the g-secretase complex presenilin 1 (psen1), presenilin 2 (psen2), nicastrin (ncstn), presenilin enhancer 2 homolog (psenen) and aph1a, and for Abdegrading enzymes such as neprilysin (mme) and cathepsin D (CTSD).…”

Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells

“…The functions of nuclear MMPs are still poorly understood, although recent studies have explained some of them . No data are so far available regarding the functions of nuclear MMP2/9 in malignant mesothelioma cells.…”

“…Recent work has uncovered nontraditional roles for MMPs in the extracellular space as well as in the cytosol and nucleus . Several studies have shown that novel nuclear MMPs are associated with apoptosis . Increased nuclear gelatinolytic activity is associated with the processing of the DNA repair enzyme poly‐ADP‐ribose polymerase‐1 (PARP‐1), which protects cells from apoptosis and DNA fragmentation …”

Matrix metalloproteinase‐7 in periodontitis with type 2 diabetes mellitus

“…Strong positive staining of the nucleus was observed in samples collected from the T2DM/GP group as compared to those from the control group. Nuclear localization of MMP7 has been associated with aggressive migration of cancer cells and decreased wound healing in cancer tissues . Although pathogenesis of cancer and periodontitis are not comparable, cell migration (pocket formation) and decreased wound healing are observed in patients with periodontitis with T2DM as well.…”