Dimerization of Matrix Metalloproteinase-2 (MMP-2)

Koo, Bon‐Hun; Kim, Yeon Hyang; Han, Jung Ho; Kim, Doo-Sik

doi:10.1074/jbc.m111.337949

Cited by 27 publications

(8 citation statements)

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“…Immunoblotting showed increase in MMP‐2 expression in the CR and MILD phenotypes compared with sham and was further increased in the MOD phenotype compared with sham, CR, and MILD. Furthermore, there was increase in the dimerization of MMP‐2 in the MOD phenotype, which has been shown to correlate with increased MMP‐2 activity24 (Figure 5A). MMP‐9 expression was increased and TIMP‐1 expression was decreased in the MOD phenotype only (Figure 5A).…”

Section: Resultsmentioning

confidence: 83%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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BackgroundFollowing pressure overload, compensatory concentric left ventricular remodeling (CR) variably transitions to eccentric remodeling (ER) and systolic dysfunction. Mechanisms responsible for this transition are incompletely understood. Here we leverage phenotypic variability in pressure overload–induced cardiac remodeling to test the hypothesis that altered mitochondrial homeostasis and calcium handling occur early in the transition from CR to ER, before overt systolic dysfunction.Methods and ResultsSprague Dawley rats were subjected to ascending aortic banding, (n=68) or sham procedure (n=5). At 3 weeks post–ascending aortic banding, all rats showed CR (left ventricular volumes < sham). At 8 weeks post–ascending aortic banding, ejection fraction was increased or preserved but 3 geometric phenotypes were evident despite similar pressure overload severity: persistent CR, mild ER, and moderate ER with left ventricular volumes lower than, similar to, and higher than sham, respectively. Relative to sham, CR and mild ER phenotypes displayed increased phospholamban, S16 phosphorylation, reduced sodium‐calcium exchanger expression, and increased mitochondrial biogenesis/content and normal oxidative capacity, whereas moderate ER phenotype displayed decreased p‐phospholamban, S16, increased sodium‐calcium exchanger expression, similar degree of mitochondrial biogenesis/content, and impaired oxidative capacity with unique activation of mitochondrial autophagy and apoptosis markers (BNIP3 and Bax/Bcl‐2).ConclusionsAfter pressure overload, mitochondrial biogenesis and function and calcium handling are enhanced in compensatory CR. The transition to mild ER is associated with decrease in mitochondrial biogenesis and content; however, the progression to moderate ER is associated with enhanced mitochondrial autophagy/apoptosis and impaired mitochondrial function and calcium handling, which precede the onset of overt systolic dysfunction.

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Section: Resultsmentioning

confidence: 83%

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Chaanine

Nair

Bergen

et al. 2017

JAHA

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“…Also, in cultured rat cardiomyocytes, treatment with IgG obtained from preeclamptic women enhances AT 1 R-mediated response, which is ameliorated with the PKC inhibitor calphostin C, further supporting a role of PKC in preeclampsia [87]. Studies have also shown that EGF and PKC could promote MMP dimerization [28]. The present study support a role of EGFR/PKC pathway in the observed MMP-9 homodimerization because: 1) In placenta, uterus, and uterine artery of Preg rats, treatment with EGFR inhibitor or PKC inhibitor reduced the gelatinolytic activity of 200 kDa MMP-9 homodimer.…”

Section: Discussionmentioning

confidence: 99%

“…Also, MMPs are often secreted in an inactive pro-form that undergoes proteolytic activation by other MMPs and proteases to the active form [18, 25]. MMP-2 could undergo dimerization and form complexes with other MMPs or even TIMPs [28–32, 35–38]. Also, MMP-9 may undergo homodimerization as well as complexation with other proteins [33, 34].…”

Section: Discussionmentioning

confidence: 99%

“…Also, endogenous TIMPs bind to and inhibit MMPs [26, 27]. Also, the gelatinases MMP-2 and MMP-9 are secreted from cells as monomers which could form various complexes and dimeric forms [28–34]. Of note, activation of gelatinases may require the formation of non-inhibitory complexes with other MMPs or TIMPs [35, 36].…”

Section: Introductionmentioning

confidence: 99%

“…2) HTN-Preg is associated with changes in MMP-9 homodimer and MMP-9/TIMP complex in placenta, uterus and uterine artery. 3) Epidermal growth factor (EGF) receptor (EGFR) and protein kinase C (PKC) have been implicated in MMP dimerization [28]. Therefore, we tested whether modulators of the EGFR/PKC pathway affect the formation and activity of MMP-9 homodimer and MMP-9/TIMP complex in Preg and RUPP rats.…”

Section: Introductionmentioning

confidence: 99%

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Decreased homodimerization and increased TIMP-1 complexation of uteroplacental and uterine arterial matrix metalloproteinase-9 during hypertension-in-pregnancy

Chen

Ren

Zhu

et al. 2017

Biochemical Pharmacology

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Preeclampsia is a complication of pregnancy manifested as hypertension-in-pregnancy (HTN-Preg) and often intrauterine growth restriction (IUGR). Placental ischemia could be an initiating event, but the molecular mechanisms are unclear. To test the hypothesis that dimerization of matrix metalloproteinases (MMPs) plays a role in HTN-Preg and IUGR, the levels/activity of MMP-9, tissue inhibitor of metalloproteinase (TIMP-1), and their dimerization forms were measured in the placenta, uterus, and uterine artery of normal pregnant (Preg) rats and a rat model of reduced uteroplacental perfusion pressure (RUPP). Consistent with our previous report, blood pressure (BP) was higher, pup weight was lower, and gelatin zymography showed different gelatinolytic activity for pro-MMP-9, MMP-9, pro-MMP-2 and MMP-2 in RUPP vs Preg rats. Careful examination of the zymograms showed additional bands at 200 and 135 kDa. Western blots with MMP-9 antibody suggested that the 200 kDa band was a MMP-9 homodimer. Western blots with TIMP-1 antibody as well as reverse zymography suggested that the 135 kDa band was a MMP-9/TIMP-1 complex. The protein levels and gelatinase activity of MMP-9 homodimer were decreased while MMP-9/TIMP-1 complex was increased in placenta, uterus and uterine artery of RUPP vs Preg rats. The epidermal growth factor (EGF) receptor blocker erlotinib and protein kinase C (PKC) inhibitor bisindolylmaleimide decreased MMP-9 homodimer and increased MMP-9/TIMP-1 complex in placenta, uterus and uterine artery of Preg rats. EGF and the PKC activator phorbol-12,13-dibutyrate (PDBu) reversed the decreases in MMP-9 homodimer and the increases in MMP-9/TIMP-1 complex in tissues of RUPP rats. Thus, the increased BP and decreased pup weight in placental ischemia model of HTN-Preg are associated with a decrease in MMP-9 homodimer and an increase in MMP-9/TIMP-1 complex in placenta, uterus, and uterine artery, which together would cause a net decrease in MMP-9 activity and reduce uteroplacental and vascular remodeling in the setting of HTN-Preg and IUGR. Enhancing EGFR/PKC signaling may reverse the MMP-9 unfavorable dimerization patterns and thereby promote uteroplacental and vascular remodeling in preeclampsia.

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Human Protein Kinase CK2 Phosphorylates Matrix Metalloproteinase 2 and Inhibits its Activity

Filipiak¹,

Kubiński²,

Hellman³

et al. 2014

ChemBioChem

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Matrix metalloproteinase 2 (MMP-2) is involved in cancer development and is overexpressed in a variety of malignant tumors. MMP-2 activity is controlled mainly by transcription, proteolytic activation, and inhibition by endogenous inhibitors. It had previously been demonstrated that MMP-2 activity is also regulated by phosphorylation at several sites by protein kinase C. Here we demonstrate, by means of bioinformatics and biochemical and cellular assays, that protein kinase CK2 also acts as a modulator of MMP-2 activity. CK2 down-regulates MMP-2 in vitro, and inhibition of CK2 in human fibrosarcoma cells results in up-regulation of MMP-2. The discovery of the crosstalk between MMP-2 and CK2 opens the possibility of new combined anticancer therapies.

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Dimerization of Matrix Metalloproteinase-2 (MMP-2)

Cited by 27 publications

References 50 publications

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

Decreased homodimerization and increased TIMP-1 complexation of uteroplacental and uterine arterial matrix metalloproteinase-9 during hypertension-in-pregnancy

Human Protein Kinase CK2 Phosphorylates Matrix Metalloproteinase 2 and Inhibits its Activity

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