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*601500
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SMOOTHENED, DROSOPHILA, HOMOLOG OF; SMOH
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| Alternative titles; symbols |
| SMO |
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| HGNC Approved Gene Symbol: SMO |
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Cytogenetic location: 7q32.1
Genomic coordinates (GRCh37): 7:128,828,712-128,853,385 (from NCBI)
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| Gene-Phenotype Relationships |
| Location |
Phenotype |
Phenotype
MIM number |
Inheritance
(in progress) |
Phenotype
mapping key |
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7q32.1
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Basal cell carcinoma, somatic
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3
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| TEXT |
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Cloning and Expression
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Stone et al. (1996) screened a rat embryonic library with the Drosophila 'Smoothened' (Smo) gene and isolated overlapping cDNA clones which encoded a protein of 794 amino acids. Subsequently they isolated a human homolog of the Drosophila Smo gene, which is 94% homologous to the rat gene. The rat and human SMO genes are 33% homologous to Drosophila Smo; in the putative transmembrane domains of the gene homology is 50%. Stone et al. (1996) reported that human and rat SMO appear to be 7-transmembrane G protein-coupled receptors with 4 glycosylation sites and a putative extracellular amino terminus 203-205 amino acids long which includes 13 cysteines and can bind a polypeptide ligand. They observed that the spatial distribution of the rat 'Patched' gene product PTC (601309) and SMO show considerable overlap in embryonic tissues.  |
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Gene Structure
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| Xie et al. (1998) reported that the human SMOH locus occupies more than 35 kb of genomic DNA. They found that the human SMOH gene is composed of 12 exons within 24 kb of genomic DNA. Exons 1 and 2 contain 5-prime untranslated sequences, the initiation codon ATG, and the entire signal peptide. |
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Gene Function
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Stone et al. (1996) carried out competitor binding, crosslinking, and coprecipitation studies and demonstrated that there was no evidence that Smo acted as a receptor for Shh (600725), the Sonic hedgehog gene product. They demonstrated that an epitope-tagged N-terminal Shh peptide binds specifically to mouse Ptc (601309). They also showed that Ptc and Smo form a complex to which Shh binds. Stone et al. (1996) noted that genetic mutations leading to a truncated or unstable Ptc protein are associated with the familial or sporadic form of basal cell carcinoma (BCC). This finding, combined with the fact that Ptc is a high-affinity binding protein for Shh, suggests that the hedgehog system may provide mitogenic or differentiative signals to basal cells in the skin throughout life. Stone et al. (1996) raised the possibility that BCNS (109400) and BCC might result from constitutive activation of SMO, which then becomes oncogenic after its release from inhibition by PTC.
On the basis of their studies in Drosophila, Chen and Struhl (1996) presented evidence that Ptc acts as a receptor for hedgehog (Hh) proteins. They suggested a novel signal transduction mechanism in which Hh proteins bind to Ptc or to a Ptc-Smo complex and thereby induce Smo activity.
Taipale et al. (2002) reported that Ptc and Smo are not significantly associated with hedgehog-responsive cells and that free Ptc (unbound by hedgehog) acts substoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a 12-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters. Taipale et al. (2002) demonstrated that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. Taipale et al. (2002) suggested that the Ptc tumor suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.
Chen et al. (2004) found that 2 molecules interact with mammalian Smo in an activation-dependent manner: G protein-coupled receptor kinase-2 (GRK2; 109635) leads to phosphorylation of Smo, and beta-arrestin-2 (ARRB2; 107941) fused to green fluorescent protein interacts with Smo. These 2 processes promote endocytosis of Smo in clathrin-coated pits. Ptc inhibits association of Arrb2 with Smo, and this inhibition is relieved in cells treated with Shh. A Smo agonist stimulated and a Smo antagonist (cyclopamine) inhibited both phosphorylation of Smo by Grk2 and interaction of Arrb2 with Smo. Chen et al. (2004) suggested that Arrb2 and Grk2 are thus potential mediators of signaling by activated Smo.
Jia et al. (2004) showed that PKA (see 188830) and casein kinase I (CKI; 600505) regulate Smo cell surface accumulation and activity in response to hedgehog (Hh; see Shh, 600725). Blocking PKA or CKI activity in the Drosophila wing disc prevented Hh-induced Smo accumulation and attenuated pathway activity, whereas increasing PKA activity promoted Smo accumulation and pathway activation. Jia et al. (2004) showed that PKA and CKI phosphorylate Smo at several sites, and that phosphorylation-deficient forms of Smo fail to accumulate on the cell surface and are unable to transduce the Hh signal. Conversely, phosphorylation-mimicking Smo variants showed constitutive cell surface expression and signaling activity. Furthermore, Jia et al. (2004) found that the levels of Smo cell surface expression and activity correlated with its levels of phosphorylation. Jia et al. (2004) concluded that Hh induces progressive Smo phosphorylation by PKA and CKI, leading to elevation of Smo cell surface levels and signaling activity.
Corbit et al. (2005) showed that mammalian Smo is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Shh or activating mutations in Smo promoted ciliary localization, whereas the Smo antagonist cyclopamine inhibited ciliary localization. They showed that the translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain shown to be required for the ciliary localization of 7-transmembrane proteins in C. elegans. Mutation of this domain not only prevented ciliary localization but also eliminated Smo activity both in cultured cells and in zebrafish embryos. Thus, Corbit et al. (2005) concluded that Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium.
Using an assay for G protein activation sensitive for receptor-constitutive activity, Riobo et al. (2006) found that mouse Smo coupled with all members of the Gi family (see 139310), but not with members of other G protein families. Inhibitors of hedgehog signaling blocked coupling of Smo with Gi. In addition, Gi and the C-terminal tail of Smo were required for activation of Gli (165220). Riobo et al. (2006) proposed that SMO is the source of 2 signals, one operating through Gi and the other originating with the SMO C-terminal tail, that are required for activation of GLI.
Zhao et al. (2007) provided evidence that phosphorylation by hedgehog activates SMO by inducing a conformational switch in Drosophila melanogaster. This occurs by antagonizing multiple arg clusters in the SMO cytoplasmic tail. The arg clusters inhibit SMO by blocking its cell surface expression and keeping it in an inactive conformation that is maintained by intramolecular electrostatic interactions. Hedgehog-induced phosphorylation disrupts the interaction and induces a conformational switch and dimerization of SMO cytoplasmic tails, which is essential for pathway activation. Zhao et al. (2007) found that increasing the number of mutations in the arg clusters progressively activated SMO. Zhao et al. (2007) concluded that by employing multiple arg clusters as inhibitory elements counteracted by differential phosphorylation, SMO acts as a rheostat to translate graded HH signals into distinct responses.
Kovacs et al. (2008) demonstrated that beta-arrestins mediate the activity-dependent interaction of SMO and the kinesin motor protein KIF3A (604683). This multimeric complex localized to primary cilia and was disrupted in cells transfected with beta-arrestin small interfering RNA. Beta-arrestin-1 (107940) or beta-arrestin-2 (107941) depletion prevented the localization of SMO to primary cilia and the SMO-dependent activation of GLI (165220). Kovacs et al. (2008) concluded that their results suggested roles for beta-arrestin in mediating the intracellular transport of a 7-transmembrane receptor to its obligate subcellular location for signaling.
Although a cell-autonomous role for hedgehog signaling (see 600725) in tumors had been described, Yauch et al. (2008) demonstrated that hedgehog ligands failed to activate signaling in tumor epithelial cells. In contrast, their data supported ligand-dependent activation of the hedgehog pathway in the stromal microenvironment. Specific inhibition of hedgehog signaling using small molecule inhibitors, a neutralizing anti-hedgehog antibody, or genetic deletion of Smo in the mouse stroma resulted in growth inhibition in xenograft tumor models. Yauch et al. (2008) concluded that their studies demonstrated a paracrine requirement for hedgehog ligand signaling in tumorigenesis of hedgehog-expressing cancers and have important implications for the development of hedgehog pathway antagonists in cancer.
Ogden et al. (2008) presented in vitro and in vivo evidence in Drosophila that Smoothened activates G-alpha-i (139310) to modulate intracellular cAMP levels in response to hedgehog. Ogden et al. (2008) concluded that Smoothened functions as a canonical G protein-coupled receptor, which signals through GNAI1 to regulate hedgehog pathway activation.
Zhao et al. (2009) demonstrated that the loss of Smo, an essential component of the hedgehog pathway, impairs hematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia (CML; 608232) by the BCR-ABL1 (see 151410) oncoprotein. Loss of Smo causes depletion of CML stem cells, which propagate the leukemia, whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, Zhao et al. (2009) showed that the cell fate determinant Numb (603728), which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacologic inhibition of hedgehog signaling impairs not only the propagation of CML driven by wildtype BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. Zhao et al. (2009) concluded that hedgehog pathway activity is required for maintenance of normal and neoplastic stem cells of the hematopoietic system and raised the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.
Resistance of Bcr (151410)-Abl (189980)-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML; 608232) can cause relapse of disease and might be the origin for emerging drug-resistant clones. Dierks et al. (2008) identified Smo as a drug target in Bcr-Abl-positive LSCs. They showed that Hedgehog signaling is activated in LSCs through upregulation of Smo. While nullity for Smo does not affect long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacologic Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Dierks et al. (2008) postulated that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML.
The centrosome is essential for cytotoxic T lymphocyte function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunologic synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog signaling. Lymphocytes do not form primary cilia, but de la Roche et al. (2013) found that Hedgehog signaling plays an important role in cytotoxic T lymphocyte killing. T cell receptor activation, which 'prearms' cytotoxic T lymphocytes with cytotoxic granules, also initiated Hedgehog signaling through IHH (600726), PTCH1 (601309), and SMOH, which are localized on intracellular vesicles that polarize toward the immunologic synapse. Hedgehog pathway activation occurred intracellularly and triggered RAC1 (602048) synthesis. These events 'prearmed' cytotoxic T lymphocytes for action by promoting the actin remodeling required for centrosome polarization and granule release. De la Roche et al. (2013) concluded that Hedgehog signaling plays a role in cytotoxic T lymphocyte function and that the immunologic synapse may represent a modified cilium. |
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Biochemical Features
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Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and other human tumors are associated with mutations that activate the protooncogene 'Smoothened' or that inactivate the tumor suppressor 'Patched.' Smoothened and Patched mediate the cellular response to the hedgehog secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the hedgehog response pathway. Taipale et al. (2000) showed that the plant-derived teratogen cyclopamine, which inhibits the hedgehog response, is a potential mechanism-based therapeutic agent for treatment of these tumors. Taipale et al. (2000) showed that cyclopamine or synthetic derivatives with improved potency block activation of the hedgehog response pathway and abnormal cell growth associated with both types of oncogenic mutation. Taipale et al. (2000) concluded that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.
Crystal Structure
Wang et al. (2013) reported the crystal structure of the transmembrane domain of the human SMO receptor bound to a small molecule antagonist at 2.5-angstrom resolution. Although the SMO receptor shares the 7-transmembrane helical fold, most of the conserved motifs for class A GPCRs are absent, and the structure revealed an unusually complex arrangement of long extracellular loops stabilized by 4 disulfide bonds. The ligand binds at the extracellular end of the 7-transmembrane-helix bundle and forms extensive contacts with the loops. |
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Mapping
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| By fluorescence in situ hybridization (FISH), Quirk et al. (1997) mapped the human SMOH gene to 7q32. By the same method, Xie et al. (1998) mapped the gene to 7q31-q32. By FISH and radiation hybrid analysis, Sublett et al. (1998) refined the localization to 7q32.3. |
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Molecular Genetics
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| Basal cell carcinomas are the commonest human cancer. Insight into their genesis came from identification of mutations in the Patched gene in patients with the basal cell nevus syndrome, a hereditary disease characterized by multiple basal cell carcinomas and by developmental abnormalities. The binding of Sonic hedgehog to its receptor, PTCH, is thought to prevent normal inhibition by PTCH of smoothened (SMOH), a 7-transmembrane protein. According to this model, the inhibition of SMOH signaling is relieved following mutational inactivation of PTCH in basal cell nevus syndrome. Xie et al. (1998) identified activating somatic missense mutations in the SMOH gene itself in sporadic basal cell carcinomas from 3 patients. The mutant SMOH, unlike wildtype, can cooperate with adenovirus E1A to transform rat embryonic fibroblast cells in culture. Furthermore, skin abnormalities similar to basal cell carcinomas developed in transgenic murine skin overexpressing mutant SMOH. These findings support the role of SMOH as a signaling component of the SHH-receptor complex and provide direct evidence that mutated SMOH can function as an oncogene in basal cell carcinomas. |
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Animal Model
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To gain insight into the role of SMO in hedgehog signaling in vertebrates, Zhang et al. (2001) generated a null allele of Smo by gene targeting in mouse embryonic stem (ES) cells. They showed that Smo acts epistatic to Ptc1 to mediate Shh and Ihh (600726) signaling in the early mouse embryo. Smo and Shh/Ihh compound mutants had identical phenotypes: embryos failed to turn, arresting at somite stages with a small, linear heart tube, an open gut, and cyclopia. The absence of visible left/right (L/R) asymmetry led the authors to examine the pathways controlling L/R situs. Zhang et al. (2001) presented evidence consistent with a model in which hedgehog signaling within the node is required for activation of GDF1 (602880) and induction of left-side determinants. Further, they demonstrated an absolute requirement for hedgehog signaling in sclerotomal development and a role in cardiac morphogenesis.
Wilbanks et al. (2004) showed that the functional knockdown of Arrb2 in zebrafish embryos recapitulates the many phenotypes of hedgehog pathway mutants. Expression of wildtype Arrb2, or constitutive activation of the hedgehog pathway downstream of Smo, rescues the phenotypes caused by Arrb2 deficiency. These results suggested to Wilbanks et al. (2004) that a functional interaction between Arrb2 and Smo may be critical to regulate hedgehog signaling in zebrafish development. |
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| ALLELIC VARIANTS (2 Selected Examples): |
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Table View
ClinVar
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.0001
BASAL CELL CARCINOMA, SPORADIC
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SMOH, TRP535LEU
[dbSNP:rs121918347]
[ClinVar]
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| Xie et al. (1998) identified a trp535-to-leu (W535L) mutation in the seventh transmembrane domain of the SMOH protein in a sporadic basal cell carcinoma from each of 2 patients. Xie et al. (1998) referred to this mutant SMOH as SMO-M2. |
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.0002
BASAL CELL CARCINOMA, SPORADIC
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SMOH, ARG562GLN
[dbSNP:rs121918348]
[ClinVar]
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| Xie et al. (1998) identified an arg562-to-gln (R562Q) mutation in the C-terminal cytoplasmic tail of SMOH in a sporadic basal cell carcinoma. Xie et al. (1998) referred to this mutation as SMO-M1. |
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| REFERENCES |
| 1. |
Chen, W., Ren, X.-R., Nelson, C. D., Barak, L. S., Chen, J. K., Beachy, P. A., de Sauvage, F., Lefkowitz, R. J.
Activity-dependent internalization of Smoothened mediated by beta-arrestin 2 and GRK2.
Science 306: 2257-2260, 2004.
[PubMed: 15618519, related citations]
[Full Text]
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| 2. |
Chen, Y., Struhl, G.
Dual roles for Patched in sequestering and transducing hedgehog.
Cell 87: 553-563, 1996.
[PubMed: 8898207, related citations]
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| 3. |
Corbit, K. C., Aanstad, P., Singla, V., Norman, A. R., Stainier, D. Y. R., Reiter, J. F.
Vertebrate Smoothened functions at the primary cilium.
Nature 437: 1018-1021, 2005.
[PubMed: 16136078, related citations]
[Full Text]
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| 4. |
de la Roche, M., Ritter, A. T., Angus, K. L., Dinsmore, C., Earnshaw, C. H., Reiter, J. F., Griffiths, G. M.
Hedgehog signaling controls T cell killing at the immunological synapse.
Science 342: 1247-1250, 2013.
[PubMed: 24311692, related citations]
[Full Text]
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| 5. |
Dierks, C., Beigi, R., Guo, G.-R., Zirlik, K., Stegert, M. R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., Warmuth, M.
Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation.
Cancer Cell 14: 238-249, 2008.
[PubMed: 18772113, related citations]
[Full Text]
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| 6. |
Jia, J., Tong, C., Wang, B., Luo, L., Jiang, J.
Hedgehog signalling activity of Smoothened requires phosphorylation by protein kinase A and casein kinase I.
Nature 432: 1045-1050, 2004.
[PubMed: 15616566, related citations]
[Full Text]
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| 7. |
Kovacs, J. J., Whalen, E. J., Liu, R., Xiao, K., Kim, J., Chen, M., Wang, J., Chen, W., Lefkowitz, R. J.
Beta-arrestin-mediated localization of Smoothened to the primary cilium.
Science 320: 1777-1781, 2008.
[PubMed: 18497258, related citations]
[Full Text]
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| 8. |
Ogden, S. K., Fei, D. L., Schilling, N. S., Ahmed, Y. F., Hwa, J., Robbins, D. J.
G protein G-alpha-i functions immediately downstream of Smoothened in hedgehog signalling.
Nature 456: 967-970, 2008.
[PubMed: 18987629, related citations]
[Full Text]
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| 9. |
Quirk, J., van den Heuvel, M., Henrique, D., Marigo, V., Jones, T. A., Tabin, C., Ingham, P. W.
The Smoothened gene and hedgehog signal transduction in Drosophila and vertebrate development.
Cold Spring Harbor Symp. Quant. Biol. 62: 217-226, 1997.
[PubMed: 9598354, related citations]
[Full Text]
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| 10. |
Riobo, N. A., Saucy, B., DiLizio, C., Manning, D. R.
Activation of heterotrimeric G proteins by Smoothened.
Proc. Nat. Acad. Sci. 103: 12607-12612, 2006.
[PubMed: 16885213, related citations]
[Full Text]
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| 11. |
Stone, D. M., Hynes, M., Armanini, M., Swanson, T. A., Gu, Q., Johnson, R. L., Scott, M. P., Pennica, D., Goddard, A., Phillips, H., Noll, M., Hooper, J. E., de Sauvage, F., Rosenthal, A.
The tumour-suppressor gene Patched encodes a candidate receptor for Sonic hedgehog.
Nature 384: 129-134, 1996.
[PubMed: 8906787, related citations]
[Full Text]
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| 12. |
Sublett, J. E., Entrekin, R. E., Look, A. T., Reardon, D. A.
Chromosomal localization of the human Smoothened gene (SMOH) to 7q32.3 by fluorescence in situ hybridization and radiation hybrid mapping.
Genomics 50: 112-114, 1998.
[PubMed: 9628830, related citations]
[Full Text]
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| 13. |
Taipale, J., Chen, J. K., Cooper, M. K., Wang, B., Mann, R. K., Milenkovic, L., Scott, M. P., Beachy, P. A.
Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine.
Nature 406: 1005-1009, 2000.
[PubMed: 10984056, related citations]
[Full Text]
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| 14. |
Taipale, J., Cooper, M. K., Maiti, T., Beachy, P. A.
Patched acts catalytically to suppress the activity of Smoothened.
Nature 418: 892-897, 2002. Note: Erratum: Nature 420: 445 only, 2002.
[PubMed: 12192414, related citations]
[Full Text]
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| 15. |
Wang, C., Wu, H., Katritch, V., Han, G. W., Huang, X.-P., Liu, W., Siu, F. Y., Roth, B. L., Cherezov, V., Stevens, R. C.
Structure of the human smoothened receptor bound to an antitumour agent.
Nature 497: 338-343, 2013.
[PubMed: 23636324, related citations]
[Full Text]
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| 16. |
Wilbanks, A. M., Fralish, G. B., Kirby, M. L., Barak, L. S., Li, Y.-X., Caron, M. G.
Beta-arrestin 2 regulates zebrafish development through the hedgehog signaling pathway.
Science 306: 2264-2267, 2004.
[PubMed: 15618520, related citations]
[Full Text]
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| 17. |
Xie, J., Murone, M., Luoh, S.-M., Ryan, A., Gu, Q., Zhang, C., Bonifas, J. M., Lam, C.-W., Hynes, M., Goddard, A., Rosenthal, A., Epstein, E. H., Jr., de Sauvage, F. J.
Activating Smoothened mutations in sporadic basal-cell carcinoma.
Nature 391: 90-92, 1998.
[PubMed: 9422511, related citations]
[Full Text]
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| 18. |
Yauch, R. L., Gould, S. E., Scales, S. J., Tang, T., Tian, H., Ahn, C. P., Marshall, D., Fu, L., Januario, T., Kallop, D., Nannini-Pepe, M., Kotkow, K., Marsters, J. C., Jr., Rubin, L. L., de Sauvage, F. J.
A paracrine requirement for hedgehog signalling in cancer.
Nature 455: 406-410, 2008.
[PubMed: 18754008, related citations]
[Full Text]
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| 19. |
Zhang, X. M., Ramalho-Santos, M., McMahon, A. P.
Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node.
Cell 105: 781-792, 2001.
[PubMed: 11440720, related citations]
[Full Text]
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| 20. |
Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T.
Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia.
Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009.
[PubMed: 19169242, related citations]
[Full Text]
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| 21. |
Zhao, Y., Tong, C., Jiang, J.
Hedgehog regulates smoothened activity by inducing a conformational switch.
Nature 450: 252-258, 2007.
[PubMed: 17960137, related citations]
[Full Text]
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| ▸ Contributors: |
Ada Hamosh - updated : 01/30/2014 |
|
Ada Hamosh - updated : 8/27/2013
Ada Hamosh - updated : 8/27/2009
Ada Hamosh - updated : 4/28/2009
Ada Hamosh - updated : 2/18/2009
Ada Hamosh - updated : 10/2/2008
Ada Hamosh - updated : 7/17/2008
Ada Hamosh - updated : 1/9/2008
Paul J. Converse - updated : 11/9/2006
Ada Hamosh - updated : 11/21/2005
Ada Hamosh - updated : 3/3/2005
Ada Hamosh - updated : 1/14/2005
Ada Hamosh - updated : 9/13/2002
Stylianos E. Antonarakis - updated : 7/2/2001
Carol A. Bocchini - updated : 3/21/1999
Carol A. Bocchini - updated : 12/1/1998
Victor A. McKusick - updated : 9/30/1998
Moyra Smith - updated : 11/19/1996 |
| Creation Date: |
Moyra Smith : 11/13/1996 |
| ▸ Edit History: |
alopez : 01/30/2014 |
|
alopez : 8/27/2013
alopez : 8/27/2013
carol : 4/22/2013
alopez : 9/8/2009
terry : 8/27/2009
alopez : 5/6/2009
terry : 4/28/2009
alopez : 2/20/2009
terry : 2/18/2009
alopez : 11/6/2008
terry : 10/8/2008
alopez : 10/6/2008
terry : 10/2/2008
alopez : 7/21/2008
terry : 7/17/2008
alopez : 1/28/2008
terry : 1/9/2008
mgross : 11/14/2006
terry : 11/9/2006
alopez : 11/21/2005
terry : 11/21/2005
alopez : 3/4/2005
terry : 3/3/2005
alopez : 1/18/2005
alopez : 1/18/2005
terry : 1/14/2005
alopez : 9/13/2002
carol : 11/24/2001
mgross : 7/2/2001
alopez : 9/5/2000
terry : 3/22/1999
carol : 3/21/1999
terry : 12/2/1998
carol : 12/1/1998
carol : 10/5/1998
terry : 9/30/1998
alopez : 7/31/1998
dkim : 7/30/1998
mark : 1/6/1997
mark : 11/19/1996
mark : 11/14/1996
mark : 11/13/1996 |
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