Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The action radius of matrix metalloproteinases or MMPs is not restricted to massive extracellular matrix (ECM) degradation, it extends to the proteolysis of numerous secreted and membrane-bound proteins. Although many instances exist in which cells disintegrate, often in conjunction with induction of MMPs, the intracellular MMP substrate repertoire or degradome remains relatively unexplored. We started an unbiased exploration of the proteolytic modification of intracellular proteins by MMPs, using gelatinase B/MMP-9 as a model enzyme. To this end, multidimensional degradomics technology was developed by the integration of broadly available biotechniques. In this way, 100-200 MMP-9 candidate substrates were isolated, of which 69 were identified. Integration of these results with the known biological functions of the substrates revealed many novel MMP-9 substrates from the intracellular matrix (ICM), such as actin, tubulin, gelsolin, moesin, ezrin, Arp2/3 complex subunits, filamin B and stathmin. About 2/3 of the identified candidates were autoantigens described in multiple autoimmune conditions and in cancer (e.g. annexin I, nucleolin, citrate synthase, HMGB1, alpha-enolase, histidyl-tRNA synthetase, HSP27, HSC70, HSP90, snRNP D3). These findings led to the insight that MMPs and other proteases may have novel (immuno)regulatory properties by the clearance of toxic and immunogenic burdens of abundant ICM proteins released after extensive necrosis. In line with the extracellular processing of organ-specific autoantigens, proteolysis might also assist in the generation of immunodominant 'neo-epitopes' from systemic autoantigens. The study of proteolysis of ICM molecules, autoantigens, alarmins and other crucial intracellular molecules may result in the discovery of novel roles for proteolytic modification.
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PMID:Multidimensional degradomics identifies systemic autoantigens and intracellular matrix proteins as novel gelatinase B/MMP-9 substrates. 2002 47

The interleukin-6 (IL-6)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway mediates cell proliferation and migration. S-phase kinase-associated protein-2 (Skp2) catalyzes the ubiquitylation of p27 and p21. Here we investigated that the cross-talk of the two pathways regulates motility and invasion of gastric cancer SGC7901 and MGC803 cells. Both cell lines endogenously secret IL-6, and blockage of IL-6 or JAK2 inhibited the activation of JAK2 and STAT3. Depletion of STAT3 downregulated Skp2 expression, and thereby increased the expression of p27 and p21. The depletion of STAT3 inhibited the ability of cells to migrate and invade, and impaired the cellular cytoskeleton mainly microtubules; while the depletion of p27 partially restored the impaired ability to migrate, and reversed the impaired microfilaments, further inhibited the ability to invade, but had little effect on microtubules and cellular adhering ability of STAT3-depleted cells. STAT3 depletion inhibited the activity of RhoA and the interaction with stathmin, downregulated the expression of pFAK (phosphorylated focal adhesion kinase), acetylated-tubulin, RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and Sp1, upregulated E-cadherin, and reduced the activities of MMP (matrix metalloproteinase)-2 and -9. The depletion of p27 increased RhoA (Ras homolog family member A) activity, upregulated RECK, and downregulated E-cadherin and Sp1 in STAT3-depleted cells. The results indicate that the interaction between STAT3 and Skp2/p27/p21 pathway plays an important role in mediating the motility, migration and invasion of gastric cancer cells, and inhibition of STAT3 may be a useful therapeutic approach for metastasis of gastric cancer, but caution needs to be taken for its effects on Skp2/p27/p21 pathway.
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PMID:STAT3 interacts with Skp2/p27/p21 pathway to regulate the motility and invasion of gastric cancer cells. 2333 63