* 601267
CHEMOKINE, CC MOTIF, RECEPTOR 2; CCR2
Alternative titles; symbols
CMKBR2
CKR2
MONOCYTE CHEMOTACTIC PROTEIN 1 RECEPTOR
MCP1 RECEPTOR
Other entities represented in this entry:
HGNC Approved Gene Symbol: CCR2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:46,354,111-46,360,940 (from NCBI)
Gene-Phenotype Relationships
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | {HIV infection, susceptibility/resistance to} | 609423 | 3 | |
| Polycystic lung disease | 219600 | Autosomal recessive | 3 |
TEXT
Description
The CCR2 gene encodes a 7-transmembrane G-protein coupled receptor for CCL2 (158105) that is expressed on human monocytes, dendritic cells, and basophils (summary by Neehus et al., 2024).
Monocyte chemoattractant protein-1 (MCP1, or CCL2; 158105) is produced by endothelial cells, smooth muscle cells, and macrophages in response to a variety of mediators. It may be involved in inflammatory processes in rheumatoid arthritis, alveolitis, and tumor infiltration, and it may also be an important component of monocyte invasion of artery walls in atherosclerosis. CCR2 encodes a receptor for MCP1 (Charo et al., 1994).
Cloning and Expression
Charo et al. (1994) isolated 2 cDNAs by degenerate PCR using primers for a conserved region in the second and third transmembrane domains of the MIP-1-alpha/RANTES receptor (CCR1; 601159) and IL-8 receptors (146928, 146929). They then used PCR products to screen a human monocytic leukemia-cell library. The 2 cDNAs encoded putative chemokine receptors (termed A and B) that are identical except for their C termini and thus appear to result from alternative splicing. The 347-amino acid predicted protein from the A isoform, designated MCP1RA (and later termed CC CKR2A by Combadiere et al., 1995), is 51% identical to the MIP-1-alpha/RANTES receptor. As are the other members of this receptor family, MCP1RA is a 7-transmembrane G protein-coupled receptor.
By examining the genomic structure of the CCR2 gene, Wong et al. (1997) confirmed that the CCR2A and CCR2B isoforms are the result of alternative splicing. Both isoforms share a common 5-prime end composed of exon 1 and the 5-prime half of exon 2, but differ in their carboxyl tails and 3-prime untranslated regions. In transfected cells, CCR2B is expressed at the cell surface and in the cytoplasm, while CCR2A is found almost exclusively in the cytoplasm.
Neehus et al. (2024) found that CCR2 was expressed in monocytic and dendritic cell precursors in the early stages of embryonic hematopoiesis, but not in more terminally differentiated cells, such as macrophages.
Gene Function
Combadiere et al. (1995) demonstrated that the predominant agonist for CC CKR2A is MCP1, while both MCP1 and MCP3 (158106) are ligands for the CC CKR2B isoform (Combadiere et al., 1995).
Wong et al. (1997) found that both CCR2A and CCR2B mediated agonist-dependent calcium mobilization and adenylyl cyclase inhibition in signaling studies.
By expressing CCR2A or CCR2B in Jurkat cells, Sanders et al. (2000) determined that MCP1 bound to both isoforms with high affinity but that 5-fold less MCP1 induced chemotaxis in CCR2B-expressing cells compared to CCR2A-expressing cells. The chemotactic response in both cases was pertussis toxin sensitive, suggesting that Gi-alpha (139310) is involved in this response. MCP1 induced calcium flux in cells expressing CCR2B but not in cells expressing CCR2A, suggesting that calcium flux may not be required for MCP1-induced chemotaxis.
Using yeast 2-hybrid and coimmunoprecipitation analyses and fluorescence microscopy, Terashima et al. (2005) showed that human FROUNT (NUP85; 170285) bound to the membrane-proximal C-terminal domain of activated CCR2 and facilitated cluster formation at the cell front during chemotaxis. Overexpression of FROUNT amplified the chemokine-elicited PI3K (see 601232)-RAC (602048)-lamellipodium protrusion cascade and subsequent chemotaxis, whereas blocking FROUNT by using a truncated mutant or antisense strategy diminished CCR2 signaling. Suppression of Frount in a mouse model of peritonitis inhibited macrophage infiltration.
By phylogenetic analysis, Toda et al. (2009) found that the C-terminal region of CCR5 (601373) has high homology to that of CCR2. Yeast 2-hybrid and coimmunoprecipitation analyses demonstrated that the CCR2-binding domain of FROUNT bound to the C termini of CCR2 and CCR5, but not to those of CCR1, CCR3 (601268), or CXCR4 (162643). Toda et al. (2009) concluded that FROUNT is a common regulator of CCR2 and CCR5.
Tacke et al. (2007) analyzed mouse monocyte subsets in apoE (107741) -/- mice and traced their differentiation and chemokine receptor usage as they accumulated in atherosclerotic lesions. ApoE -/- mice showed increased monocyte counts that skewed toward an increased frequency of Ccr2-positive monocytes in mice fed a high-fat diet. Ccr2-positive monocytes accumulated efficiently into atherosclerotic plaques, whereas Ccr2-negative monocytes infrequently entered plaques, but were more prone to developing into plaque cells expressing the dendritic cell marker Cd11c (ITGAX; 151510). Ccr2-negative monocytes used Ccr5 rather than Cx3cr1 (601470) to enter plaques, whereas Ccr2-positive cells required Cx3cr1 for plaque entry. Tacke et al. (2007) proposed that CX3CR1 antagonism may be effective therapeutically in ameliorating CCR2-positive monocyte recruitment to plaques.
Using flow cytometry and ELISA, Sato et al. (2007) found that CCR2-positive, but not CCR2-negative, CD4 (186940)-positive T cells produced IL17 (603149). Within the CCR2-positive population, CCR5-positive cells produced IFNG (147570) and CCR5-negative cells produced IL17. Sato et al. (2007) concluded that human Th17 cells are CCR2-positive/CCR5-negative.
Qian et al. (2011) defined the origin of metastasis-associated macrophages by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumors in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2, the receptor for chemokine CCL2 (158105), as well as the subsequent recruitment of metastasis-associated macrophages and their interaction with metastasizing tumor cells, is dependent on CCL2 synthesized by both the tumor and the stroma. Inhibition of CCL2-CCR2 signaling blocked the recruitment of inflammatory monocytes, inhibited metastasis in vivo, and prolonged the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibited metastatic seeding. Inflammatory monocytes promote the extravasation of tumor cells in a process that requires monocyte-derived vascular endothelial growth factor (VEGF; 192240). CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer. Qian et al. (2011) suggested that their data provide the mechanistic link between these 2 clinical associations.
Biochemical Features
Crystal Structure
Zheng et al. (2016) solved a structure of CCR2 in a ternary complex with an orthosteric (BMS-681) and allosteric (CCR2-RA-[R]) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a theretofore unseen binding mode. Zheng et al. (2016) observed that CCR2-RA-[R] binds in a novel, highly druggable pocket that was the most intracellular allosteric site observed in class A G protein-coupled receptors to that time; this site spatially overlaps the G protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 noncompetitively by blocking activation-associated conformational changes and formation of the G protein-binding interface.
Gene Structure
Wong et al. (1997) determined that the CCR2 gene comprises 3 exons spanning approximately 7 kb of genomic sequence.
Mapping
By FISH, Daugherty and Springer (1997) determined that the CMKBR1 (601159), CMKBR2, and CMKBR3 (601268) genes are clustered within 285 kb on 3p21.
Molecular Genetics
Polymorphisms
Identification of the CC-chemokines RANTES (187011), MIP1-alpha (182283), and MIP1-beta (182284) as suppressor factors produced by CD8 cells that counter infection by certain HIV-1 strains (see 609423) facilitated the identification of 2 chemokine receptors, CXCR4 (or fusin; 162643) and CCR5, as cell surface coreceptors with CD4 in HIV-1 infection. Additional receptors, CCR2 and CCR3 (601268), were also implicated as HIV-1 coreceptors on certain cell types (Choe et al., 1996; Doranz et al., 1996). The findings in CCR5 and CXCR4 prompted a search for polymorphisms in other chemokine receptor genes that mediate disease progression. Smith et al. (1997) identified a val64-to-ile polymorphism (64I; 601267.0001) in the first transmembrane region of CCR2, at an allele frequency of 10 to 15% among Caucasians and African Americans. Studies of 2 cohorts of AIDS patients showed that the CCR2-64I allele exerted no influence on the incidence of HIV-1 infection, but that HIV-1 infected persons carrying the 64I allele progressed to AIDS 2 to 4 years later than persons homozygous for the more common allele. The CCR2 gene maps to 3p21.3 within approximately 17.5 kb of CCR5 (Samson et al. (1996, 1996)). Smith et al. (1997) analyzed 2-locus genotypes and found that the 32-bp deletion at the CCR5 locus (601373.0001) and the 64I allele at the CCR2 locus are in strong, perhaps complete, linkage disequilibrium with each other. This means that CCR5-del32 invariably occurs on a chromosome with allele CCR2-64V, whereas CCR2-64I occurs on a chromosome that has the wildtype (undeleted) allele at the CCR5 locus. Thus, they could estimate the independent effects of the CCR2 and CCR5 polymorphisms. Rapid progression of less than 3 years from HIV-1 exposure to onset of AIDS symptoms in an estimated 38 to 45% of AIDS patients could be attributed to their wildtype status at one or the other of these loci, whereas the survival of 28 to 29% of long-term survivors, who avoided AIDS for 16 years or more, could be explained by a mutant genotype for CCR2 or CCR5.
Polycystic Lung Disease
In 9 patients from 5 unrelated families with polycystic lung disease (PCLUD; 219600), Neehus et al. (2024) identified homozygous or compound heterozygous mutations in the CCR2 gene (601267.0002-601267.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. There were 3 missense mutations, 1 frameshift, and 1 small in-frame deletion that were scattered throughout the gene. Transduction of the mutations into CCR2-null THP1 monocytic cells showed that all resulted in absent CCR2A/CCR2B expression. In addition, none of the variants was able to rescue defective CCL2-stimulated Ca2+ mobilization in CCR2-null cells. CCR2 was not detected on patient monocytes, peripheral blood mononuclear cells (PBMCs), or in lung tissue. Patient monocytes showed poor or absent response to CCL2 stimulation, including lack of Ca2+ mobilization, poor migration, and impaired phosphorylation of downstream kinases, indicating functional deficits. Bronchoalveolar lavage (BAL) in 4 patients showed low proportions of alveolar macrophages (almost a 50% decrease compared to controls), possibly due to impaired migration of monocytes. The patients also had increased serum levels of CCL2, consistent with complete CCR2 deficiency. Total blood leukocyte and differential cell counts, immunoglobulins, and gamma-IFN production were normal in all patients. Hematopoiesis was not disrupted and other monocyte and macrophage functions (production of ROS and phagocytosis) were unaffected. Neehus et al. (2024) concluded that complete CCR2 deficiency increases the risk of pulmonary infection likely due to reduced numbers of tissue-resident monocyte-derived macrophages resulting from impaired monocyte migration and recruitment to the lungs. The reduced number of alveolar macrophages is unable to clear surfactant, leading to features of pulmonary alveolar proteinosis (PAP) in some patients. Accompanying constrictive peribronchiolar lymphocytosis and mild fibrosis results in obstruction of the terminal bronchioles, increased airway pressure, alveolar enlargement, and the formation of cysts.
Animal Model
Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation. In addition to their function in viral disease, as describe above, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine MCP1 is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolemic diet, and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP1 is causally related to the development of atherosclerosis, Boring et al. (1998) generated mice that lacked CCR2, the receptor for MCP1, and crossed them with mice null for apoE, which develop severe atherosclerosis. They found that the selective absence of CCR2 decreased lesion formation markedly in apoE -/- mice but had no effect on plasma lipid or lipoprotein concentrations. These data revealed a role for MCP1 in the development of early atherosclerotic lesions and suggested that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidemia and fatty streak formation.
Peters et al. (2000) observed that after immunization with Th1-inducing agents, Ccr2 -/- mice produced markedly less gamma-interferon (IFNG; 147570) after antigen-specific stimulation than did wildtype mice. In contrast, IL5 (147850), IL10 (124092), and IL13 (147683) production was not impaired in Ccr2 -/- mice. Flow cytometric analysis showed that fewer antigen-presenting cells migrated to the immunization site or draining lymph nodes in the Ccr2 -/- mice. Peters et al. (2000) concluded that CCR2 is required for proper trafficking of antigen-presenting cells capable of inducing IFNG production by T cells.
Peters et al. (2001) presented evidence from knockout mice that cellular responses mediated by activation of CCR2 are essential in the initial immune response and control of infection by Mycobacterium tuberculosis. Ccr2 -/- mice died early after infection and had 100-fold more bacteria in their lungs than did wildtype mice. The homozygous-null mice exhibited an early defect in macrophage recruitment to the lung and a later defect in recruitment of dendritic cells and T cells to the lung.
Stein et al. (2003) injected cationized low density lipoprotein (LDL) into a leg muscle of Ccr2-null mice to determine the role of macrophages in cholesterol clearance in atherosclerosis. They found that Ccr2-null mice had reduced cholesterol clearance due to decreased cholesteryl ester (CE) hydrolysis, which is mandatory prior to cholesterol efflux. Immunocytochemical analysis indicated that the deficits correlated with delayed recruitment of macrophages to the injection site. CE hydrolysis and macrophage cell numbers were also significantly reduced in thioglycollate-elicited peritoneal exudate cells of Ccr2-null mice. Stein et al. (2003) concluded that recruitment of macrophages is required for LDL cholesterol clearance during regression of an atheroma.
Abbadie et al. (2003) assessed pain behavior in Ccr2-deficient mice in models of inflammatory and neuropathic pain. They found that Ccr2-deficient mice did not develop mechanical allodynia associated with nerve ligation, had a significant reduction of the second phase of the flinching response evoked by intraplantar formalin, and exhibited a modest attenuation of mechanical allodynia produced by Freund adjuvant inflammation. They proposed that CCR2 may be a useful target for the treatment of neuropathic pain.
Ambati et al. (2003) found that mice lacking either Mcp1 or its receptor, Ccr2, developed cardinal features of age-related macular degeneration (ARMD; see, e.g., 153800), including accumulation of lipofuscin in, and drusen beneath, the retinal pigmented epithelium (RPE), photoreceptor atrophy, and choroidal neovascularization. In addition there was an age-related accumulation of complement components and IgG in the RPE of the knockout mice, perhaps reflecting dysfunction in macrophage recruitment.
To elucidate the relative contributions of CCR2 and CCR5 in collagen-induced arthritis and collagen antibody-induced arthritis, Quinones et al. (2004) genetically inactivated the 2 receptors in an arthritis-prone murine strain. Contrary to expectations, they found that Ccr2-null mice had markedly enhanced susceptibility to both collagen-induced and collagen antibody-induced arthritis, whereas the Ccr5-null mice had an arthritis phenotype similar to that of wildtype mice. Quinones et al. (2004) concluded that CCR2 serves a protective role in rheumatoid arthritis and that there are likely alternative receptors responsible for monocyte/macrophage accumulation in inflamed joints.
El Khoury et al. (2007) generated a Ccr2-deficient transgenic mice with an Alzheimer disease (AD; 104300)-associated APP mutation (104760). Both Ccr2 +/- and Ccr2 -/- APP mice demonstrated increased mortality at age 8 weeks compared to control APP mice. Ccr2 -/- APP mice had significantly increased brain beta-amyloid levels and significantly decreased levels of microglia compared to brains of control APP mice. Ccr2 -/- mononuclear phagocytes showed normal activity and proliferation, but impaired migration in response to beta-amyloid deposition. The findings indicated that Ccr2-dependent microglial accumulation plays a protective role in Alzheimer disease by mediating beta-amyloid clearance.
Binder et al. (2009) found that Ccr2-knockout mice had high bone density due to a decrease in number, size, and function of osteoclasts. In normal mice, activation of Ccr2 in osteoclast progenitor cells resulted in both NF-kappa-B (see 164011) and Erk1 (MAPK3; 601795)/Erk2 (MAPK1; 176948) signaling, which led to increased surface expression of Rank (TNFRSF11A; 603499) and increased susceptibility to Rank ligand (TNFSF11; 602642)-induced osteoclastogenesis. In wildtype ovariectomized mice, a model of postmenopausal osteoporosis, Ccr2 was upregulated on preosteoclasts, thus increasing their surface expression of Rank and osteoclastogenic potential, whereas Ccr2-knockout mice were resistant to ovariectomy-induced bone loss.
Lim et al. (2011) found that Ccr2 -/- mice exhibited a markedly increased susceptibility to West Nile virus (WNV) encephalitis (see 610379) that was associated with a selective reduction of a monocyte subset in brain. In contrast, wildtype mice, but not Ccr2 -/- mice, experienced a selective monocytosis in peripheral blood. Intravenous administration of a mixture of Ccr2 +/+ and Ccr2 -/- monocytes into WNV-infected Ccr2 -/- mice resulted in accumulation of equal amounts of the 2 types of monocytes in the central nervous system. Lim et al. (2011) concluded that CCR2 mediates highly selective peripheral blood monocytosis during WNV infection and that this is critical for monocyte accumulation in brain.
ALLELIC VARIANTS 6 Selected Examples):
.0001 HUMAN IMMUNODEFICIENCY VIRUS TYPE 1, RESISTANCE TO
SNP: rs1799864, gnomAD: rs1799864, ClinVar: RCV000008756, RCV003982833
Smith et al. (1997) demonstrated that the rarer 64I allele of a val64-to-ile polymorphism of CCR2 confers relative resistance to infection by HIV-1 (609423).
Mummidi et al. (1998) found that the CCR2-64I allele was associated with a delay in disease progression in African Americans but not in Caucasians.
.0002 POLYCYSTIC LUNG DISEASE
SNP: rs2529520604, ClinVar: RCV003984972
In 2 sisters, born of consanguineous Algerian parents (family A), with polycystic lung disease (PCLUD; 219600), Neehus et al. (2024) identified a homozygous 6-bp in-frame deletion (c.640_645del) in the CCR2 gene, resulting in the deletion of conserved residues Pro214_Leu215 in the fifth transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database (v2.1.1). In vitro studies showed that the mutation resulted in a complete loss of CCR2 expression and function.
.0003 POLYCYSTIC LUNG DISEASE
SNP: rs752561542, gnomAD: rs752561542, ClinVar: RCV003984973
In an 18-year-old girl (P9), born of consanguineous Iranian parents (family E), with polycystic lung disease (PCLUD; 219600), Neehus et al. (2024) identified a homozygous c.182T-G transversion in the CCR2 gene, resulting in a met61-to-arg (M61R) substitution at a conserved residue in the first transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. This homozygous mutation was also identified in an unrelated 12-year-old Iranian girl (P3), born of consanguineous parents (family B), who had a very mild form of the disease. The mutation was present at a low frequency (3.98 x 10(-6)). in heterozygous state in the gnomAD database (v2.1.1). In vitro studies showed that the mutation resulted in a complete loss of CCR2 expression and function. P9 had a severe phenotype, including disseminated BCG disease after vaccination and exertional dyspnea, whereas P3 had local BCG lymphadenitis after vaccination that resolved spontaneously and no dyspnea or pulmonary symptoms at 13 years of age.
.0004 POLYCYSTIC LUNG DISEASE
SNP: rs2529521725, ClinVar: RCV003984974
In 2 brothers, born of consanguineous Iranian parents (family C), with polycystic lung disease (PCLUD; 219600), Neehus et al. (2024) identified a homozygous c.887C-A transversion in the CCR2 gene, resulting in a thr296-to-asn (T296N) substitution at a conserved residue in the seventh transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the gnomAD database (v2.1.1). In vitro studies showed that the mutation resulted in a complete loss of CCR2 expression and function.
.0005 POLYCYSTIC LUNG DISEASE
SNP: rs1268159081, ClinVar: RCV003984975
In 3 sisters, born of unrelated parents (family D) from the US, with polycystic lung disease (PCLUD; 219600), Neehus et al. (2024) identified compound heterozygous mutations in the CCR2 gene: a 2-bp insertion (c.59_60insAC), resulting in a frameshift and premature termination (Thr21ProfsTer18) in the extracellular N-terminal domain, and a c.356T-G transversion, resulting in a leu119-to-arg (L119R; 601267.0006) substitution at a conserved residue in the third transmembrane domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in the homozygous state in gnomAD (v2.1.1). In vitro studies showed that the mutations resulted in a complete loss of CCR2 expression and function.
.0006 POLYCYSTIC LUNG DISEASE
SNP: rs113340633, ClinVar: RCV003984976
For discussion of the c.356T-G transversion in the CCR2 gene, resulting in a leu119-to-arg (L119R) substitution, that was found in compound heterozygous state in 3 sisters with polycystic lung disease (PCLUD; 219600) by Neehus et al. (2024), see 601267.0005.
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Ada Hamosh - updated : 01/10/2017
Paul J. Converse - updated : 11/9/2012
Paul J. Converse - updated : 2/13/2012
Ada Hamosh - updated : 8/24/2011
Patricia A. Hartz - updated : 4/24/2009
Paul J. Converse - updated : 11/13/2008
Cassandra L. Kniffin - updated : 5/1/2007
Paul J. Converse - updated : 4/12/2007
Marla J. F. O'Neill - updated : 8/9/2005
Cassandra L. Kniffin - updated : 10/29/2003
Victor A. McKusick - updated : 7/16/2003
Patricia A. Hartz - updated : 3/11/2003
Victor A. McKusick - updated : 8/17/2001
Paul J. Converse - updated : 7/6/2001
Paul J. Converse - updated : 1/31/2001
Victor A. McKusick - updated : 11/9/1999
Carol A. Bocchini - updated : 3/21/1999
Victor A. McKusick - updated : 9/8/1998
Jennifer P. Macke - updated : 12/2/1997
Victor A. McKusick - updated : 8/14/1997
carol : 03/12/2024
ckniffin : 03/06/2024
alopez : 03/09/2022
alopez : 01/10/2017
mgross : 12/04/2012
terry : 11/9/2012
mgross : 2/15/2012
terry : 2/13/2012
alopez : 8/25/2011
terry : 8/24/2011
mgross : 4/29/2009
terry : 4/24/2009
mgross : 11/17/2008
terry : 11/13/2008
wwang : 6/6/2007
ckniffin : 5/1/2007
mgross : 4/12/2007
mgross : 4/12/2007
carol : 8/9/2005
mgross : 6/16/2005
terry : 4/5/2005
alopez : 11/7/2003
tkritzer : 10/31/2003
ckniffin : 10/29/2003
cwells : 7/24/2003
terry : 7/16/2003
mgross : 3/14/2003
terry : 3/11/2003
mgross : 9/26/2002
mcapotos : 8/28/2001
mcapotos : 8/17/2001
mgross : 7/6/2001
mcapotos : 2/7/2001
mcapotos : 1/31/2001
terry : 12/1/1999
terry : 11/9/1999
alopez : 7/27/1999
terry : 3/22/1999
carol : 3/21/1999
carol : 9/14/1998
terry : 9/8/1998
dkim : 7/24/1998
alopez : 1/5/1998
alopez : 12/22/1997
alopez : 12/12/1997
alopez : 12/12/1997
alopez : 11/18/1997
alopez : 10/7/1997
mark : 8/14/1997
mark : 8/14/1997
mark : 8/14/1997
jenny : 4/8/1997
mark : 8/30/1996
terry : 6/21/1996
terry : 5/22/1996
terry : 5/21/1996
terry : 5/21/1996
terry : 5/21/1996