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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane type-1 matrix metalloproteinase (MT1-MMP) is the prototypical member of a subgroup of membrane-anchored proteinases that belong to the matrix metalloproteinase family. Although synthesized as a zymogen, MT1-MMP plays an essential role in extracellular matrix remodeling after an undefined process that unmasks its catalytic domain. We now report the existence of a proprotein convertase-MT1-MMP axis that regulates the processing and functional activity of the metalloproteinase. Two sets of basic motifs in the propeptide region of MT1-MMP are identified that potentially can be recognized by the proprotein convertase family of subtilisin-like proteases. Processing of proMT1-MMP as well as the expression of its proteolytic activity were blocked by mutating these recognition motifs or by inhibiting the proprotein convertases furin and PC6 with the serpin-based inhibitor alpha(1) antitrypsin Portland. Furthermore, both furin-dependent and furin-independent MT1-MMP processing pathways are identified that require tethering of the metalloproteinase to the cell surface. These findings demonstrate the existence of a proprotein convertase-MT1-MMP axis that can regulate extracellular matrix remodeling.
Mol Biol Cell 2000 Jul
PMID:Regulation of membrane type-1 matrix metalloproteinase activation by proprotein convertases. 1088 76

Processing of latent precursor proteins by proprotein convertases (PCs) into their biologically active products is a common mechanism required for many important biologic functions. This process is tightly regulated, leading to the generation of active peptides and proteins including neuropeptides and polypeptide hormones, protein tyrosine phosphatases, growth factors and their receptors, and enzymes including matrix metalloproteases (MMPs). These processing reactions occurs at pairs of basic amino acids. Within the past several years, a novel family of Ca(2+)-dependent serine proteases has been identified, all of which possess homology to the endoproteases subtilisin (bacteria) and kexin (yeast). This family of PCs is currently comprised of fewer than a dozen members, known as furin/paired basic amino-acid-cleaving enzyme (PACE), PC1/PC3, PC2, PC4, PACE4, PC5/PC6, and PC7/PC8/lymphoma proprotein convertase. They share a high degree of amino-acid identity of 50-75% within their catalytic domains. Despite the relatively high degree of homology in the PC family, only PACE4 and furin localize to the same chromosome: mouse chromosome 7 and human chromosome 15. Recent reports have supported a possible functional role for PCs in tumorigenesis. For instance, convertases have been shown to be expressed in various tumor lines and human primary tumors. Furin and PACE4 process stromelysin 3 (MMP-11 or Str-3), an MMP involved in tumor invasion, into its mature, active form. Similarly, a growing family of MMPs, known as membrane-type metalloproteinases (MT-MMPs), and growth factors and adhesion molecules such as E-cadherin show similar amino-acid motifs and thus could be activated by furin and PACE4. These data, taken together with the high expression levels of PACE4 in 50% of murine chemically induced spindle cell tumors, confer to PACE4 and possibly other PCs a possible functional role in the activation of MMPs and consequently in tumor cell invasion and tumor progression. This was further supported by the remarkable enhancement in the invasive ability of the PACE4-transfected murine tumor cell lines. Mol. Carcinog. 28:63-69, 2000.
Mol Carcinog 2000 Jun
PMID:The proprotein convertases furin and PACE4 play a significant role in tumor progression. 1090 Apr 62

Members of the kexin family of processing enzymes are responsible for the cleavage of many proproteins during their transport through the secretory pathway. The enzymes are themselves made as inactive precursors and we have investigated the activation of Krp1, a kexin from the fission yeast Schizosaccharomyces pombe. As Krp1 is essential for cell growth, we have used a krp1ts strain to investigate the role of the prosequence in the activation process. Mutations that reduce either the efficiency with which the prosequence is released or the rate at which the released prosegment is subsequently cleaved at an internal site are less active when assayed in vivo. We also show that prosegments lacking an internal dibasic motif can act as autoinhibitors and prevent activation of the catalytic fragment. Krp1 constructs containing prosequences based on these inhibitors do not become active in vitro. Surprisingly, the same constructs do become active in the intact cell and appear to suggest that alternative activation processes can be used by these enzymes.
Mol Microbiol 2000 Aug
PMID:A temperature-sensitive Krp1 allows in vivo characterization of kexin activation. 1093 54

Many secretory proteins are synthesized as inactive proproteins that undergo proteolytic activation as they travel through the eukaryotic secretory pathway. The best characterized family of processing enzymes are the prohormone convertases or kexins, and these are responsible for the processing of a wide variety of prohormones and other precursors. Recent work has identified other proteases that appear to be involved in proprotein processing, but characterization of these enzymes is at an early stage. Krp1 is the only kexin identified in the fission yeast Schizosaccharomyces pombe, in which it is essential for cell viability. We have used a genetic screen to identify four proteases with specificities that overlap Krp1. Two are serine proteases, one is a zinc metalloprotease (glycoprotease) and one is an aspartyl protease that belongs to the recently described yapsin family of processing enzymes. All four proteases support the growth of a yeast strain lacking Krp1, and each is able to process the P-factor precursor, the only substrate currently known to be processed by Krp1.
Mol Microbiol 2000 Nov
PMID:Identification of proteases with shared functions to the proprotein processing protease Krp1 in the fission yeast Schizosaccharomyces pombe. 1111 18

Two proprotein convertase cDNAs, PC1 and furin, were stably transfected into the human breast cancer cell line MCF-7. The PC1 or furin over-expressing cells possessed an altered morphology. When grown in vitro in a serum-free medium, the population doubling time of the convertase-transfected cells was twice that of wild-type (WT) cells. High concentrations of estradiol stimulated the growth of all three cell types to a similar extent; however, at low concentrations of estradiol, the convertase-transfected cells grew more slowly than WT cells. In athymic nude mice implanted with 5 mg estradiol pellets, the growth of tumors of convertase-transfected MCF-7 cells was stimulated to a degree similar to that of WT MCF-7 tumors. However, in mice implanted with lower-dose (1.5 mg) estradiol pellets, the tumors of PC1- or furin-transfected MCF-7 cells grew approximately five times slower than those of WT MCF-7 cells. In mice implanted with tamoxifen pellets, tumors of PC1- or furin-transfected MCF-7 cells regressed approximately five times slower than the WT tumors. This study shows that the over-expression of proprotein convertases confers a greater estrogen dependency and anti-estrogen resistance on human breast cancer cells.
J Mol Endocrinol 2001 Apr
PMID:Elevated expression of proprotein convertases alters breast cancer cell growth in response to estrogen and tamoxifen. 1124 Nov 61

Prohormone convertase 3 (PC3) is a neuroendocrine-specific member of the subtilisin-kexin family, involved in the intracellular processing and maturation of prohormones and proneuropeptides. PC3 is synthesised as a proprotein that undergoes two different cleavages resulting in the mature PC3 and the enzymatically active PC3DeltaC. In vitro translated proPC3 and proPC3DeltaC bind to trans-Golgi network (TGN)/granule-enriched membranes from the AtT20 neuroendocrine cell line in a pH-dependent manner suggesting both a dominant role for the pro-region in membrane association and that the C-terminal region is not essential. However, while PC3 bound to membranes the majority of PC3DeltaC did not, suggesting that either the pro-region or the C-terminal region of PC3 is required for membrane association. Removal of peripheral membrane proteins did not affect the binding properties of any of the in vitro translated proteins. Chromaffin granule membranes (CGMs) were used to study the binding characteristics of endogenous PC3 and its active C-terminal truncated counterpart (PC3DeltaC). Incubation of CGMs with Triton X-100 did not completely solubilise either of these forms of PC3. Moreover, both PC3 and PC3DeltaC remained associated with detergent-resistant membrane microdomains, termed lipid rafts, purified from CGMs. The data raise the possibility that PC3 and PC3DeltaC are sorted to the regulated secretory pathway via their association with membrane lipid rafts.
J Mol Endocrinol 2001 Aug
PMID:Association of prohormone convertase 3 with membrane lipid rafts. 1146 81

We cloned and sequenced a gene, kpcA (Kex2p-like proprotein convertase A), from a genomic library of Aspergillus nidulans. The kpcA gene encodes an 820-residue protein, named KpcA, which contains a putative subtilisin-like catalytic domain (residues 136-466) homologous to that of the subtilisin serine protease family. KpcA shows 56, 73, and 47% amino acid identities with Saccharomyces cerevisiae Kex2p, Aspergillus niger KexB, and mouse furin within the subtilisin-like catalytic domain, respectively. The sequences around the proposed active site Asp, His, and Ser residues of KpcA are similar to those of other Kex2p family members. The KpcA mRNA transcript with an expected size of approximately 2.8 kb was detected in A. nidulans. The substrate specificity of KpcA, expressed in CHO cells, is similar to that of A. niger KexB and yeast Kex2p. We conclude that KpcA is a resident Kex2p-like proprotein that processes endoprotease in A. nidulans.
Mol Cells 2001 Aug 31
PMID:Molecular cloning of kpcA gene encoding a Kex2p-like endoprotease from Aspergillus nidulans. 1156 25

Pneumocystis carinii is fungus which is a frequent cause of severe pneumonia in immunocompromised individuals. The P. carinii genome contains the PRT1 subtelomeric multigene family that encodes a kexin-like serine protease which is expressed on the surface of P. carinii. Analysis of the sequence of the carboxy-terminal sequence of many copies of PRT1 showed that they contained motifs characteristic of a glycosylphosphatidylinositol (GPI) anchor signal sequence. The ability of the C-terminal sequences of PRT1 to direct the addition of a GPI anchor was tested. CD14, a GPI-anchored monocyte glycoprotein antigen, was used as the basis of a heterologous system. CD14 was truncated to remove the carboxy-terminal sequences responsible for GPI-anchor addition. Addition of carboxy-terminal sequences from PRT1 restored high-level surface expression to the truncated CD14. Further, the majority of CD14-PRT1 recombinant protein was removed from the cell membrane by treatment with GPI-specific phospholipase C. These results suggest that the carboxy-terminal residues of most of the members of the PRT1 family of proteases have the potential to form a functional GPI-attachment signal.
Am J Respir Cell Mol Biol 2001 Oct
PMID:Functional glycosylphosphatidylinositol anchor signal sequences in the Pneumocystis carinii PRT1 protease family. 1169 52

The proprotein convertase PC2 is primarily expressed in neuroendocrine cells where it mediates the proteolytic maturation of prohormones and proneuropeptides. We have identified in the upstream sequence of its gene a conserved domain partially homologous to the repressor element RE1/NRSE found in several genes for neuronal proteins. RE1/NRSE binds the silencing transcription factor REST/NRSF, a nuclear protein primarily found in nonneuronal cells. To determine the functionality of the PC2 gene RE1-like sequence (RE1-lk), we examined by electrophoretic mobility shift assays its ability to attach nuclear factors from PC2-expressing and nonexpressing cells. Specific binding factors were mostly detectable in PC2-non-expressing cells. These factors differ from REST/NRSF, as molar excess of competing RE1/NRSE could not prevent their binding to RE1-lk. Reciprocally, molar excess of RE1-lk could not prevent the binding of RE1/NRSE to the DNA-binding domain of a recombinant REST/NRSF. The presence of RE1-lk in cis reduced the ability of the PC2 promoter and the heterologous phosphoglycerate kinase promoter to drive expression of a green fluorescent protein reporter gene in transiently transfected PC2-nonexpressing cells, but not in PC2-expressing cells. These observations suggest that binding of transcription-silencing factors to the RE1-lk element may contribute to repression of the PC2 gene in nonneuroendocrine cells.
Brain Res Mol Brain Res 2002 Jun 15
PMID:Characterization of a repressor element in the promoter region of proprotein convertase 2 (PC2) gene. 1219 92

Three glycoproteins (ZP1, ZP2, and ZP3) are synthesized in growing mouse oocytes and secreted to form an extracellular zona pellucida that mediates sperm binding and fertilization. Each has a signal peptide to direct it into a secretory pathway, a "zona" domain implicated in matrix polymerization and a transmembrane domain from which the ectodomain must be released. Using confocal microscopy and enhanced green fluorescent protein (EGFP), the intracellular trafficking of ZP3 was observed in growing mouse oocytes. Replacement of the zona domain with EGFP did not prevent secretion of ZP3, suggesting the presence of trafficking signals and a cleavage site in the carboxyl terminus. Analysis of linker-scanning mutations of a ZP3-EGFP fusion protein in transient assays and in transgenic mice identified an eight-amino-acid hydrophobic region required for secretion and incorporation into the zona pellucida. The hydrophobic patch is conserved among mouse zona proteins and lies between a potential proprotein convertase (furin) cleavage site and the transmembrane domain. The cleavage site that releases the ectodomain from the transmembrane domain was defined by mass spectrometry of native zonae pellucidae and lies N-terminal to a proprotein convertase site that is distinct from the hydrophobic patch.
Mol Cell Biol 2003 Dec
PMID:Mutation of a conserved hydrophobic patch prevents incorporation of ZP3 into the zona pellucida surrounding mouse eggs. 1464 11


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