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BACKGROUND: Matrix metalloproteinases (MMPs) are members of the superfamily of Zn2+ dependent extracellular or membrane-bound endopeptidases which have been implicated to play critical roles in vertebrate development and human pathogenesis. A number of MMP genes have been found to be upregulated in some or all organs during frog metamorphosis, suggesting that different MMPs may have different functions in various organs/tissues. The recent advances in EST (expressed sequence tag) sequencing and the completion of the genome of Xenopus (X.) tropicalis prompted us to systematically analyze the existence of MMPs in the Xenopus genome.
RESULTS: We examined X. laevis and X. tropicalis ESTs and genomic sequences for MMPs and obtained likely homologs for 20 out of the 25 MMPs known in higher vertebrates. Four of the five missing MMPs, i.e. MMPs 8, 10, 12 and 27, were all encoded on human Chromosome 11 and the other missing MMP, MMP22 (a chicken MMP), was also absent in human genome. In addition, we identified several novel MMPs which appears to be derived from unique duplications over evolution, are present in the genomes of both Xenopus species.
CONCLUSION: We identified the homologs of most of the mammalian MMPs in Xenopus and discovered a number of novel MMPs. Our results suggest that MMP genes undergo dynamic changes over evolution. It will be of interest in the future to investigate whether MMP expression and functions during vertebrate development are conserved. The sequence information reported here should facilitate such an endeavor in the near future.
Figure 1. Phylogenetic tree of X. tropicalis (Xt) and human MMPs. Also included are chicken MMP22 (cMMP22) and Rana catesbeiana MMP1 (Rc-MMP1) as MMP22 was not found in human and Xenopus and Rc-MMP1 has a unique sequence organization (see description on MMP1). Novel X. tropicalis MMPs are highlighted in bold.
Figure 2. Sequence comparison of MMP1 with MMP N4 and MMP N5. X. tropicalis (Xt) MMP1, N4 and N5, and X. laevis (Xl) MMP1A and 1B were aligned with human (h) MMP1 for comparison. The sequences of the putative signal peptide are underlined. The predicted cleavage site between the signal peptide and the propeptide is indicated by an arrow, and the predicted cleavage site between the propeptide and the catalytic domain is indicated by solid arrowhead. The conserved sequence in the propeptide involved in the cysteine-switch is boxed, and the zinc-binding motif within the bracketed catalytic domain is indicated by a solid line on top. The three conserved histidine residues in the zinc binding motif and the conserved methionine residue of the nearby Met-turn are indicated by stars below. The 16 aa sequence (shadowed) at the end of the catalytic domain (bracketed) indicates the region whose integrity is important for collagenase specificity for collagen. An insertion of 8 or more aa within this region at the site indicated by an arrowhead is characteristics of stromelysins. The arrow marked C shows the beginning of the C-terminal hemopexin-like domain. A dot indicates an identical amino acid as the corresponding one in Xt-MMP1. Gaps (dashes) are introduced to optimize the alignment among proteins. Note that MMP N4 and N5 contain internal deletions in the linker region between the catalytic domain and C-terminal hemopexin-like domain.
Figure 3. Comparison of Xenopus MMP3 with human MMP1, 3, and 10. Note that the shadowed region at the end of the catalytic domain corresponds to the same region in Fig. 2 except the insertion of 8–14 aa in stromelysins (MMP3, 10) compared to collagenases (e.g., the MMP1 shown here). See Fig. 2 for other information.
Figure 4. Comparison of frog and human MMP23 with MMP N6. The predicted signal anchor (transmembrane domain) sequences are underlined and the putative furin recognition sequences are in bold. The cysteine residues in the cysteine-array unique to MMP23 are in bold and indicated with # below. The amino acid residues characteristic of an Ig (immunoglobulin)-fold are indicated with rectangle boxes below. See Fig. 2 for other information.
Figure 5. Comparison of MMP21 with MMP N3. The predicted signal peptide is underlined and the putative furin recognition sequences within the propeptide are in bold. The sequence in white on dark background indicates the unique insertion in the propeptide in MMP21. A unique cysteine residue in the catalytic domain is in bold and indicated with a black diamond below. Note that the sequence for Xl-MMP N3 is incomplete at the N-terminus. See Fig. 2 for other information.
Figure 6. Comparison of MMP N2 with MMP7 and MMP26. Note that like human and Xenopus MMP7 and MMP26, MMP N2 lacks the linker peptide and hemopexin-like domain at the C-terminal. See Fig. 2 for other information.
Figure 7. Putative alternative splicing variant of X. laevis MMP2 (MMP2asv). A) Nucleotide and deduced amino acid sequences of MMP2asv. The protein contains, from the N-terminus to C-terminus, a signal peptide (underlined), the conserved sequence in the propeptide involved in the cysteine-switch (in bold letters), a truncated catalytic domain linked to a truncated hemopexin domain (separated by double slash lines). The predicted cleavage site between the propeptide and the catalytic domain is indicated by an arrow. B) Comparison of the full length and alternatively spliced X. laevis MMP2 exon/intron organization. Solid blocks stand for exons present in the mRNAs and lines are introns.
Figure 8. Comparison of Xenopus MMP N1 with human MMP1, 3, 12, and X. laevis MMP18. The amino acid sequence in shadowed letters corresponds to the region equivalent of the proline-rich sequences (16 aa) at the end of the catalytic domain in human MMP1 whose integrity is important for the collagenase specificity for collagen. A short peptide insertion (in bold letters) within this region is characteristics of stromelysins as shown here for MMP3. The Xenopus MMP N1 has a 16 aa-insertion within the same region (in bold letters) as well as some additional insertions within the C-terminal hemopexin-like domain (in italics). See Fig. 2 for other information.
Figure 9. Comparison of the MMPs cluster on X. tropicalis Scaffold_119 to that on human Chromosome 11. X. tropicalis MMP cDNA sequences were used to do BLAST search against the X. tropicalis genomic sequences to locate the genes on the assembly scaffolds. MMP 1, 3, 7, 13, 18, 20, 26, as well as the novel ones MMP N2, N4 and N5 are found on Scaffold_119. They were arranged on the scaffold according to their location and orientation. The human MMPs on Chromosome 11 were arranged according to the annotations for their locations and orientations in Human Genome Build 36.3 on the NCBI website. The MMPs shown above the line for the chromosome/scaffold are MMPs specific to X. tropicalis or human while those shown below are the MMPs present in both species. Mb, mega base pair; kb, kilo base pairs. Note the gene size was not drawn to scale for clarity.
Amano,
Metamorphosis-associated and region-specific expression of calbindin gene in the posterior intestinal epithelium of Xenopus laevis larva.
1998, Pubmed,
Xenbase
Amano,
Metamorphosis-associated and region-specific expression of calbindin gene in the posterior intestinal epithelium of Xenopus laevis larva.
1998,
Pubmed
,
Xenbase Basset,
Stromelysin-3: a paradigm for stroma-derived factors implicated in carcinoma progression.
1997,
Pubmed Berry,
The expression pattern of thyroid hormone response genes in remodeling tadpole tissues defines distinct growth and resorption gene expression programs.
1998,
Pubmed
,
Xenbase Berry,
The expression pattern of thyroid hormone response genes in the tadpole tail identifies multiple resorption programs.
1998,
Pubmed
,
Xenbase Damjanovski,
Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: implications for tissue-dependent functions of matrix metalloproteinases during late embryonic development.
2001,
Pubmed
,
Xenbase Damjanovski,
Spatial and temporal regulation of collagenases-3, -4, and stromelysin -3 implicates distinct functions in apoptosis and tissue remodeling during frog metamorphosis.
1999,
Pubmed
,
Xenbase de Coignac,
Cloning of MMP-26. A novel matrilysin-like proteinase.
2000,
Pubmed Fu,
Roles of Matrix Metalloproteinases and ECM Remodeling during Thyroid Hormone-Dependent Intestinal Metamorphosis in Xenopus laevis.
2007,
Pubmed
,
Xenbase Fu,
Transcriptional regulation of the Xenopus laevis Stromelysin-3 gene by thyroid hormone is mediated by a DNA element in the first intron.
2006,
Pubmed
,
Xenbase Fu,
A causative role of stromelysin-3 in extracellular matrix remodeling and epithelial apoptosis during intestinal metamorphosis in Xenopus laevis.
2005,
Pubmed
,
Xenbase Fujimoto,
One of the duplicated matrix metalloproteinase-9 genes is expressed in regressing tail during anuran metamorphosis.
2006,
Pubmed
,
Xenbase Fujimoto,
Expression of matrix metalloproteinase genes in regressing or remodeling organs during amphibian metamorphosis.
2007,
Pubmed
,
Xenbase Gururajan,
Isolation and characterization of two novel metalloproteinase genes linked to the Cdc2L locus on human chromosome 1p36.3.
1998,
Pubmed Hammoud,
Cloning and developmental characterization of Xenopus laevis membrane type-3 matrix metalloproteinase (MT3-MMP).
2006,
Pubmed
,
Xenbase Harrison,
Matrix metalloproteinase genes in Xenopus development.
2004,
Pubmed
,
Xenbase Hasebe,
Evidence for a cooperative role of gelatinase A and membrane type-1 matrix metalloproteinase during Xenopus laevis development.
2007,
Pubmed
,
Xenbase Hasebe,
Spatial and temporal expression profiles suggest the involvement of gelatinase A and membrane type 1 matrix metalloproteinase in amphibian metamorphosis.
2006,
Pubmed
,
Xenbase Hasebe,
Expression profiles of the duplicated matrix metalloproteinase-9 genes suggest their different roles in apoptosis of larval intestinal epithelial cells during Xenopus laevis metamorphosis.
2007,
Pubmed
,
Xenbase Ishizuya-Oka,
Transient expression of stromelysin-3 mRNA in the amphibian small intestine during metamorphosis.
1996,
Pubmed
,
Xenbase Ishizuya-Oka,
Requirement for matrix metalloproteinase stromelysin-3 in cell migration and apoptosis during tissue remodeling in Xenopus laevis.
2000,
Pubmed
,
Xenbase Jung,
Matrix metalloproteinases mediate the dismantling of mesenchymal structures in the tadpole tail during thyroid hormone-induced tail resorption.
2002,
Pubmed
,
Xenbase Lochter,
An odyssey from breast to bone: multi-step control of mammary metastases and osteolysis by matrix metalloproteinases.
1999,
Pubmed Loots,
ECRbase: database of evolutionary conserved regions, promoters, and transcription factor binding sites in vertebrate genomes.
2007,
Pubmed MacDougall,
Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis.
1995,
Pubmed Marchenko,
Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin.
2001,
Pubmed Matrisian,
Growth factor-regulated proteases and extracellular matrix remodeling during mammalian development.
1990,
Pubmed McCawley,
Matrix metalloproteinases: they're not just for matrix anymore!
2001,
Pubmed Mott,
Regulation of matrix biology by matrix metalloproteinases.
2004,
Pubmed Muller,
The collagenase gene family in humans consists of at least four members.
1988,
Pubmed Murphy,
Mechanisms for pro matrix metalloproteinase activation.
1999,
Pubmed Murphy,
The origin of matrix metalloproteinases and their familial relationships.
1991,
Pubmed Nagase,
Cell surface activation of progelatinase A (proMMP-2) and cell migration.
1998,
Pubmed Nagase,
Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3.
1992,
Pubmed Ohnishi,
Cloning and characterization of a rat ortholog of MMP-23 (matrix metalloproteinase-23), a unique type of membrane-anchored matrix metalloproteinase and conditioned switching of its expression during the ovarian follicular development.
2001,
Pubmed Oofusa,
Regionally and hormonally regulated expression of genes of collagen and collagenase in the anuran larval skin.
1994,
Pubmed Oofusa,
Thyroid hormone-dependent expression of bullfrog tadpole collagenase gene.
1996,
Pubmed Overall,
Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites.
2002,
Pubmed Page-McCaw,
Matrix metalloproteinases and the regulation of tissue remodelling.
2007,
Pubmed Park,
Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor.
2000,
Pubmed Patterton,
Transcriptional activation of the matrix metalloproteinase gene stromelysin-3 coincides with thyroid hormone-induced cell death during frog metamorphosis.
1995,
Pubmed
,
Xenbase Pei,
Leukolysin/MMP25/MT6-MMP: a novel matrix metalloproteinase specifically expressed in the leukocyte lineage.
1999,
Pubmed Pei,
CA-MMP: a matrix metalloproteinase with a novel cysteine array, but without the classic cysteine switch.
1999,
Pubmed Pei,
Furin-dependent intracellular activation of the human stromelysin-3 zymogen.
1995,
Pubmed Sang,
Complex role of matrix metalloproteinases in angiogenesis.
1998,
Pubmed Sarras,
Structure, expression, and developmental function of early divergent forms of metalloproteinases in hydra.
2002,
Pubmed Sato,
Membrane-type matrix metalloproteinases (MT-MMPs) in tumor metastasis.
1996,
Pubmed Saus,
The complete primary structure of human matrix metalloproteinase-3. Identity with stromelysin.
1988,
Pubmed Schreiber,
Remodeling of the intestine during metamorphosis of Xenopus laevis.
2005,
Pubmed
,
Xenbase Shapiro,
Matrix metalloproteinase degradation of extracellular matrix: biological consequences.
1998,
Pubmed Shi,
Biphasic intestinal development in amphibians: embryogenesis and remodeling during metamorphosis.
1996,
Pubmed
,
Xenbase Shi,
Regulation of extracellular matrix remodeling and cell fate determination by matrix metalloproteinase stromelysin-3 during thyroid hormone-dependent post-embryonic development.
2007,
Pubmed
,
Xenbase Shi,
Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis.
2001,
Pubmed Shi,
Thyroid hormone regulation of apoptotic tissue remodeling: implications from molecular analysis of amphibian metamorphosis.
2001,
Pubmed
,
Xenbase Shi,
The earliest changes in gene expression in tadpole intestine induced by thyroid hormone.
1993,
Pubmed
,
Xenbase Shintani,
Identification and characterization of matrix metalloproteinase-20 (MMP20; enamelysin) genes in reptile and amphibian.
2007,
Pubmed
,
Xenbase Stolow,
Identification and characterization of a novel collagenase in Xenopus laevis: possible roles during frog development.
1996,
Pubmed
,
Xenbase Tata,
Gene expression during metamorphosis: an ideal model for post-embryonic development.
1993,
Pubmed Tomlinson,
Three matrix metalloproteinases are required in vivo for macrophage migration during embryonic development.
2008,
Pubmed
,
Xenbase Tryggvason,
Proteolytic degradation of extracellular matrix in tumor invasion.
1987,
Pubmed Uria,
Matrix metalloproteinases and their expression in mammary gland.
1998,
Pubmed Van Wart,
The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family.
1990,
Pubmed Velasco,
Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members.
1999,
Pubmed Walsh,
Membrane type-1 matrix metalloproteinases and tissue inhibitor of metalloproteinases-2 RNA levels mimic each other during Xenopus laevis metamorphosis.
2007,
Pubmed
,
Xenbase Wang,
Thyroid hormone-induced gene expression program for amphibian tail resorption.
1993,
Pubmed
,
Xenbase Whitham,
Comparison of human stromelysin and collagenase by cloning and sequence analysis.
1986,
Pubmed Yang,
A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development.
1997,
Pubmed
,
Xenbase Yang,
Cloning and characterization of a novel matrix metalloproteinase (MMP), CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain.
1998,
Pubmed
,
Xenbase Yen,
Physiological and molecular basis of thyroid hormone action.
2001,
Pubmed
