Hereditary gingival fibromatosis (HGF) with hypertrichosis is unlinked to the HGF1 and HGF2 loci.
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Abnormalities, Multiple↗
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UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug.
Protein-protein interactions play critical regulatory roles in mediating signal transduction. Previous studies have identified an unconventional, small-molecule, Src signal transduction inhibitor, UCS15A. UCS15A differed from conventional Src-inhibitors in that it did not alter the levels or the tyrosine kinase activity of Src. Our studies suggested that UCS15A exerted its Src-inhibitory effects by a novel mechanism that involved the disruption of protein-protein interactions mediated by Src. In the present study we have examined the ability of UCS15A to disrupt the interaction of Src-SH3 with Sam68, both in vivo and in vitro. This ability of UCS15A was not restricted to Src-SH3 mediated protein-protein interactions, since the drug was capable of disrupting the in vivo interactions of Sam68 with other SH3 domain containing proteins such as Grb2 and PLCgamma. In addition, UCS15A was capable of disrupting other typical SH3-mediated protein-protein interactions such as Grb2-Sos1, cortactin-ZO1, as well as atypical SH3-mediated protein-protein interactions such as Grb2-Gab1. However, UCS15A was unable to disrupt the non-SH3-mediated protein-protein interactions of beta-catenin, with E-cadherin and alpha-catenin. In addition, UCS15A had no effect on the SH2-mediated interaction between Grb2 and activated Epidermal Growth Factor receptor. Thus, the ability of UCS15A, to disrupt protein-protein interactions appeared to be restricted to SH3-mediated protein-protein interactions. In this regard, UCS15A represents the first example of a non-peptide, small molecule agent capable of disrupting SH3-mediated protein-protein interactions. In vitro analyses suggested that UCS15A did not bind to the SH3 domain itself but rather may interact directly with the target proline-rich domains.
Adaptor Proteins, Signal Transducing↗
A novel locus for autosomal dominant hereditary gingival fibromatosis, GINGF3, maps to chromosome 2p22.3-p23.3.
Hereditary gingival fibromatosis (HGF) is a rare, benign disorder characterized by slowly progressive fibrous overgrowth of the gingiva. To date, two loci have been mapped in familial cases with autosomal dominant non-syndromic HGF: GINGF (MIM 135300) on chromosome 2p21-p22 and GINGF2 (MIM 605544) on chromosome 5q13-q22. Of the two loci, only SOS1 (son of sevenless one, MIM 182530) gene underlying GINGF locus has been identified. Ascertainment of a large Chinese family has allowed the mapping of a novel locus to 2p22.3-p23.3, GINGF3. Haplotype construction and analysis localized the new locus to an 11.4-cM interval between markers D2S2221 (telomeric) and D2S1788 (centromeric). The maximum two-point limit of detection (LOD) score of 3.45 (theta=0) and multipoint LOD score of 5.00 for marker D2S390 strongly supported linkage to this region. Thus, this genetic interval is distal to and does not overlap with the previously described locus, GINGF, on 2p21-p22.
Asian People↗
Characterization of fibroblasts with Son of Sevenless-1 mutation.
Although non-syndromic hereditary gingival fibromatosis (HGF) is genetically heterogeneous, etiologic mutations have been identified only in the Son of Sevenless-1 gene (SOS1). To test evidence of increased cell proliferation, we studied histological, morphological, and proliferation characteristics in monolayer and three-dimensional cultures of fibroblasts with the SOS1 g.126,142-126,143insC mutation. Histological assessment of HGF gingiva indicated increased numbers of fibroblasts (30%) and increased collagen (10%). Cell proliferation studies demonstrated increased growth rates and 5-bromo-2-deoxyuridine incorporation for HGF fibroblasts. Flow cytometry showed greater proportions of HGF fibroblasts in the G2/M phase. Attachment of HGF fibroblasts to different extracellular matrix surfaces demonstrated increased formation of protrusions with lamellipodia. HGF fibroblasts in three-dimensional culture showed greater cell proliferation, higher cell density, and alteration of surrounding collagen matrix. These findings revealed that increased fibroblast numbers and collagen matrix changes are associated with mutation of the SOS1 gene in vitro and in vivo.
Adult↗
Candidate gene association study in type 2 diabetes indicates a role for genes involved in beta-cell function as well as insulin action.
Type 2 diabetes is an increasingly common, serious metabolic disorder with a substantial inherited component. It is characterised by defects in both insulin secretion and action. Progress in identification of specific genetic variants predisposing to the disease has been limited. To complement ongoing positional cloning efforts, we have undertaken a large-scale candidate gene association study. We examined 152 SNPs in 71 candidate genes for association with diabetes status and related phenotypes in 2,134 Caucasians in a case-control study and an independent quantitative trait (QT) cohort in the United Kingdom. Polymorphisms in five of 15 genes (33%) encoding molecules known to primarily influence pancreatic beta-cell function-ABCC8 (sulphonylurea receptor), KCNJ11 (KIR6.2), SLC2A2 (GLUT2), HNF4A (HNF4alpha), and INS (insulin)-significantly altered disease risk, and in three genes, the risk allele, haplotype, or both had a biologically consistent effect on a relevant physiological trait in the QT study. We examined 35 genes predicted to have their major influence on insulin action, and three (9%)-INSR, PIK3R1, and SOS1-showed significant associations with diabetes. These results confirm the genetic complexity of Type 2 diabetes and provide evidence that common variants in genes influencing pancreatic beta-cell function may make a significant contribution to the inherited component of this disease. This study additionally demonstrates that the systematic examination of panels of biological candidate genes in large, well-characterised populations can be an effective complement to positional cloning approaches. The absence of large single-gene effects and the detection of multiple small effects accentuate the need for the study of larger populations in order to reliably identify the size of effect we now expect for complex diseases.
ATP-Binding Cassette Transporters↗
Researchers discover gene mutation responsible for hereditary gingival fibromatosis.
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Fibromatosis, Gingival↗
The putative plasma membrane Na(+)/H(+) antiporter SOS1 controls long-distance Na(+) transport in plants.
The salt tolerance locus SOS1 from Arabidopsis has been shown to encode a putative plasma membrane Na(+)/H(+) antiporter. In this study, we examined the tissue-specific pattern of gene expression as well as the Na(+) transport activity and subcellular localization of SOS1. When expressed in a yeast mutant deficient in endogenous Na(+) transporters, SOS1 was able to reduce Na(+) accumulation and improve salt tolerance of the mutant cells. Confocal imaging of a SOS1-green fluorescent protein fusion protein in transgenic Arabidopsis plants indicated that SOS1 is localized in the plasma membrane. Analysis of SOS1 promoter-beta-glucuronidase transgenic Arabidopsis plants revealed preferential expression of SOS1 in epidermal cells at the root tip and in parenchyma cells at the xylem/symplast boundary of roots, stems, and leaves. Under mild salt stress (25 mM NaCl), sos1 mutant shoot accumulated less Na(+) than did the wild-type shoot. However, under severe salt stress (100 mM NaCl), sos1 mutant plants accumulated more Na(+) than did the wild type. There also was greater Na(+) content in the xylem sap of sos1 mutant plants exposed to 100 mM NaCl. These results suggest that SOS1 is critical for controlling long-distance Na(+) transport from root to shoot. We present a model in which SOS1 functions in retrieving Na(+) from the xylem stream under severe salt stress, whereas under mild salt stress it may function in loading Na(+) into the xylem.
Arabidopsis↗
Stimulation of growth factor receptor signal transduction by activation of voltage-sensitive calcium channels.
To understand the mechanisms by which electrical activity may generate long-term responses in the nervous system, we examined how activation of voltage-sensitive calcium channels (VSCCs) can stimulate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Calcium influx through L-type VSCCs leads to tyrosine phosphorylation of the adaptor protein Shc and its association with the adaptor protein Grb2, which is bound to the guanine nucleotide exchange factor Sos1. In response to calcium influx, Shc, Grb2, and Sos1 inducibly associate with a 180-kDa tyrosine-phosphorylated protein, which was determined to be the epidermal growth factor receptor (EGFR). Calcium influx induces tyrosine phosphorylation of the EGFR to levels that can activate the MAPK signaling pathway. Thus, ion channel activation stimulates growth factor receptor signal transduction.
Adaptor Proteins, Signal Transducing↗
B cell antigen receptor cross-linking induces tyrosine phosphorylation and membrane translocation of a multimeric Shc complex that is augmented by CD19 co-ligation.
The SH2 domain-containing transforming Shc protein has been implicated in mitogenic signaling via several surface receptors through p21ras. Following tyrosine phosphorylation by either receptor or non-receptor tyrosine kinases, Shc may interact with the adaptor protein Grb2, which is linked to Sos1, a guanine nucleotide exchange factor for human ras. Ligation of the antigen receptor complex on B cells (BCR) is known to activate various intracellular signaling pathways, which may accumulate in mitogenic responses. With respect to the initial steps, the activation of BCR-associated non-receptor tyrosine kinases appears to be indispensible. In this report we show that Shc proteins become tyrosine phosphorylated after BCR ligation on both transformed and normal human B cells. This is accompanied by the association of Shc with Grb2 proteins and a yet unidentified 145-kDa tyrosine phosphorylated protein. Subcellular fractionation revealed that this activation-induced multimeric Shc complex rapidly translocates towards the plasma membrane. Co-ligation of the BCR with the CD19 molecule results in a marked increase of these events, whereas CD19 cross-linking alone does not induce Shc tyrosine phosphorylation or translocation. Thus, in B cells the Shc complex may represent a molecular junction between the BCR and the mitogenic p21ras cascade.
Adaptor Proteins, Signal Transducing↗
New approach to cancer therapy: the application of signal transduction to anti-cancer drug.
Although it has been widely known that extracellular signal-regulated kinase (ERK) pathway stimulates cell growth and have a protective effect from cell death, recent findings propose pro-apoptotic action of ERK phosphorylation. Since it was found that Vitamin K3 (VK3) or its analog was a potent growth inhibitor and inducer for ERK phosphorylation through specific pathway in cancer cell line, the critical role of ERK phosphorylation in growth inhibitory actions can be discussed. VK3 induced receptor tyrosine phosphorylation and occurred at growth inhibitory concentrations. The phosphorylation of growth factor receptor by VK3 was indicated to be functional, since these were connected with growth factor receptor-bound protein 2 (Grb2) and SOS1. The growth factor stimulated to induce cyclin D1 protein and increase DNA contents. In addition, ERK inhibitor antagonized increase of cyclin D1, suggesting that ERK phosphorylation by growth factor might play an essential role for cell growth. By contrast, ERK phosphorylation by VK3 was more prolonged and intense than the signal induced by growth factors and the antagonize ERK phosphorylation protected from growth inhibition by VK3. The additional and extra ERK spot by VK3, compared with those obtained from growth factor, was detected on two dimensional gels, and this was completely and selectively antagonized by ERK inhibitor. Therefore, the overexpressed ERK phosphorylation was suggested to originate from the additional spot, which played a critical role in growth inhibitory action, despite ERK phosphorylation by growth factor had an essential association with cell growth. The new approach to consider the signal transduction can be one of the most favorite strategies for cancer therapy in the future.
Animals↗
Light Chain 3 associates with a Sos1 guanine nucleotide exchange factor: its significance in the Sos1-mediated Rac1 signaling leading to membrane ruffling.
A 19 kDa protein was identified to associate with the Dbl oncogene homology domain of Sos1 (Sos-DH) and was purified from rat brains by GST-Sos-DH affinity chromatography. Peptide sequencing revealed that the protein is identical to light chain 3 (LC3), a microtubule-associated protein. LC3 coimmunoprecipitated with Sos1, and GST-LC3 was capable of forming complexes with Sos1 in in vitro GST-pull down assay. Furthermore, LC3 was colocalized with Sos1 in cells, as determined by immunohistochemistry. While Sos1 stimulated the guanine nucleotide exchange reaction on Rac1, LC3 suppressed the ability of Sos1 to activate Rac1 in in vitro experiments using COS cell lysates. Consistent with this, overexpression of LC3 decreased the level of active GTP-bound Rac1 in COS cells. Sos1 expression induced membrane ruffling, a downstream target for Rac1, but LC3 expression inhibited this biological effect of Sos1. These findings suggest that LC3 interacts with Sos1 and thereby negatively regulates the Sos1-dependent Rac1 activation leading to membrane ruffling.
3T3 Cells↗
Cloning of two SOS1 transporters from the seagrass Cymodocea nodosa. SOS1 transporters from Cymodocea and Arabidopsis mediate potassium uptake in bacteria.
Two cDNAs isolated from Cymodocea nodosa, CnSOS1A, and CnSOSIB encode proteins with high-sequence similarities to SOS1 plant transporters. CnSOS1A expressed in a yeast Na+-efflux mutant under the control of a constitutive expression promoter mimicked AtSOS1 from Arabidopsis; the wild type cDNA did not improve the growth of the recipient strain in the presence of Na+, but a cDNA mutant that expresses a truncated protein suppressed the defect of the yeast mutant. In similar experiments, CnSOS1B was not effective. Conditional expression, under the control of an arabinose responsive promoter, of the CnSOSIA and CnSOS1B cDNAs in an Escherichia coli mutant defective in Na+ efflux was toxic, and functional analyses were inconclusive. The same constructs transformed into an E. coli K+-uptake mutant revealed that CnSOS1A was also toxic, but that it slightly suppressed defective growth at low K+. Truncation in the C-terminal hydrophilic tail of CnSOS1A relieved the toxicity and proved that CnSOS1A was an excellent low-affinity K+ and Rb+ transporter. CnSOS1B mediated a transient, extremely rapid K+ or Rb+ influx. Similar tests with AtSOS1 revealed that it was not toxic and that the whole protein exhibited excellent K+ and Rb+ uptake characteristics in bacteria.
Amino Acid Sequence↗
Quantitative analysis of Grb2-Sos1 interaction: the N-terminal SH3 domain of Grb2 mediates affinity.
Grb2 is an adaptor protein that links receptor and cytoplasmic tyrosine kinases to the Ras signalling pathway by binding the Ras-specific guanine nucleotide exchange factor, Sos1, through its SH3 domains. The Grb2-SH3 domain binding has been localized to the carboxy-terminal two hundred amino acids of Sos1 (Sos1-c). By using real time biospecific interaction analysis (BIAcore), we studied the kinetic parameters and binding affinity of the Grb2-Sos1-c interaction. The binding of Grb2 to Sos1-c is a high affinity interaction with a moderate association rate (9.45 x 10(4) per M per s), a slow dissociation rate (13.8 x 10(-5) s), and an affinity constant of 1.48 nM. BIAcore measurements on isolated N-terminal and C-terminal SH3 domains (NSH3 and CSH3) further indicate that the high affinity Grb2-Sos1-c interaction is primarily mediated through the NSH3 domain (Kd = 1.68 nM). The CSH3 domain shows substantially reduced binding to Sos1-c in these measurements. Inhibition studies with BIAcore using proline rich peptides derived from the C-terminus of Sos1 show that there is a single major binding site for Grb2 in Sos1. This binding site is contained within the peptide N20, which corresponds to amino acids 1143-1162 of Sos1. This peptide completely blocks the Grb2-Sos1-c and NSH3-Sos1-c interactions with IC50 values of 8 microM and 4 microM respectively. The discrete interaction between the NSH3 domain and the N20 peptide may be amenable for drug discovery through screening or peptidomimetic approaches.
3T3 Cells↗
Membrane-targeting potentiates guanine nucleotide exchange factor CDC25 and SOS1 activation of Ras transforming activity.
Growth factor-triggered activation of Ras proteins is believed to be mediated by guanine nucleotide exchange factors (CDC25/GRF and SOS1/2) that promote formation of the active Ras GTP-bound state. Although the mechanism(s) of guanine nucleotide exchange factor regulation is unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. To evaluate this model, we generated constructs that encode the catalytic domains of human CDC25 or mouse SOS1, either alone (designated cCDC25 and cSOS1, respectively) or terminating in the carboxyl-terminal CAAX membrane-targeting sequence from K-Ras4B (designated cCDC25-CAAX and cSOS1-CAAX, respectively; in CAAX, C is Cys, A is an aliphatic amino acid, and X is Ser or Met). We then compared the transforming potential of cCDC25 and cSOS1 with their membrane-targeted counterparts. We observed that addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their focus-forming activity (10- to 50-fold) in NIH 3T3 transfection assays. Similarly, we observed that the membrane-targeted versions showed a 5- to 10-fold enhanced ability to induce transcriptional activation from the Ets/AP-1 Ras-responsive element. Furthermore, whereas cells that stably expressed cCDC25 or cSOS1 exhibited the same morphologies as untransformed NIH 3T3 cells, cells expressing cCDC25-CAAX or cSOS1-CAAX displayed transformed morphologies that were indistinguishable from the elongated and refractile morphology of oncogenic Ras-transformed cells. Thus, these results suggest that membrane translocation alone is sufficient to potentiate guanine nucleotide exchange factor activation of Ras.
3T3 Cells↗
Critical role of extracellular signal-regulated kinase phosphorylation on menadione (vitamin K3) induced growth inhibition.
BACKGROUND: Although it is widely known that the extracellular signal-regulated kinase (ERK) pathway stimulates cell growth and protects cells from death, recent findings have proposed a proapoptotic action of ERK phosphorylation. Because the authors found that vitamin K3 (VK3) was a potent growth inhibitor and an inducer for ERK phosphorylation through a specific pathway in the stomach cancer cell line, the critical role of ERK phosphorylation in VK(3)-mediated growth inhibitory effect was examined. METHODS: The fluorochrome Hoechst 33258 assay (Hoechst AG [now Aventis] Frankfort, Germany) was used for counting cells (excitation at 360 nm; emission at 460 nm). For two-dimensional electrophoresis, cells were dissolved in urea standard buffer and applied first to isoelectronic focusing gels. Cell lysates were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) using 10% polyacrylamide gels. To examine the phosphorylation of receptors, cell lysates were immunoprecipitated with receptor antibody. RESULTS: VK3 induced phosphorylation of hepatocyte growth factor receptor (c-met), epidermal growth factor receptor (EGFR), or external signal-regulated kinase (ERK), which increased progressively to a maximum level at 30 minutes, in a dose-dependent manner and occurred at growth inhibitory concentrations. VK(3)-mediated growth inhibition and protein tyrosine phosphorylation were nullified completely by glutathione or L-cysteine but not by nonthiol antioxidants, thus suggesting that sulfhydryl arylation might have been involved in VK(3)-mediated action. The phosphorylation of EGFR and c-met by VK(3) appeared to be functional, because these were coimmunoprecipitated with growth factor receptor-bound protein 2 (Grb2) and SOS1 antibody. Epidermal growth factor (EGF) or hepatocyte growth factor (HGF) stimulated increase of cyclin D1 protein after 12 hours and increased DNA content after 3 days in culture. In addition, U0126, which is a potent inhibitor for ERK phosphorylation, antagonized increase of cyclin D1, thus suggesting that EGF- or HGF-mediated ERK phosphorylation might have played an essential role for cell growth. By contrast, ERK phosphorylation by VK3 was more prolonged and intense than the signal induced by the growth factors. U0126 reduced ERK phosphorylation and prevented growth inhibition by VK3. Two-dimensional gels showed VK(3)-induced additional phospho-ERK spots, compared with those obtained from growth factors. This extra spot was completely antagonized by U0126. CONCLUSIONS: VK(3)-induced growth inhibition and protein tyrosine phosphorylation were mediated by the sulfhydryl arylation system. The tyrosine phosphorylation of EGFR or c-met by VK3 activated the Ras signaling pathway. The overexpressed ERK phosphorylation by VK3 seemed to originate from additional spots on two-dimensional gels, which played a critical role in VK(3)-induced growth inhibitory action despite the fact that ERK phosphorylation by growth factors had had an essential association with cell growth.
Apoptosis↗
Growth and differentiation signals regulated by the M-CSF receptor.
The normal proto-oncogene c-fms encodes the macrophage growth factor (M-CSF) receptor involved in growth, survival, and differentiation along the monocyte-macrophage lineage of hematopoietic cell development. A major portion of our research concerns unraveling the temporal, molecular, and structural features that determine and regulate these events. Previous results indicated that c-fms can transmit a growth signal as well as a signal for differentiation in the appropriate cells. To investigate the role of the Fms tyrosine autophosphorylation sites in proliferation vs. differentiation signaling, four of these sites were disrupted and the mutant receptors expressed in a clone derived from the myeloid FDC-P1 cell line. These analyses revealed that: (1) none of the four autophosphorylation sites studied (Y697, Y706, Y721, and Y807) are essential for M-CSF-dependent proliferation of the FDC-P1 clone; (2) Y697, Y706, and Y721 sites, located in the kinase insert region of Fms, are not necessary for differentiation but their presence augments this process; and (3) the Y807 site is essential for the Fms differentiation signal: its mutation totally abrogates the differentiation of the FDC-P1 clone and conversely increases the rate of M-CSF-dependent proliferation. This suggests that the Y807 site may control a switch between growth and differentiation. The assignment of Y807 as a critical site for the reciprocal regulation of growth and differentiation may provide a paradigm for Fms involvement in leukemogenesis, and we are currently investigating the downstream signals transmitted by the tyrosine-phosphorylated 807 site. In Fms-expressing FDC-P1 cells, M-CSF stimulation results in the rapid (30 sec) tyrosine phosphorylation of Fms on the five cytoplasmic tyrosine autophosphorylation sites, and subsequent tyrosine phosphorylation of several host cell proteins occurs within 1-2 min. Complexes are formed between Fms and other signal transduction proteins such as Grb2, Shc, Sos1, and p85. In addition, a new signal transduction protein of 150 kDa is detectable in the FDC-P1 cells. The p150 is phosphorylated on tyrosine, and forms a complex with Shc and Grb2. The interaction with Shc occurs via a protein tyrosine binding (PTB) domain at the N-terminus of Shc. The p150 is not detectable in Fms signaling within fibroblasts, yet the PDGF receptor induces the tyrosine phosphorylation of a similarly sized protein. In hematopoietic cells, this protein is involved in signaling by receptors for GM-CSF, IL-3, KL, MPO, and EPO. We have now cloned a cDNA for this protein and found at least one related family member. The related family member is a Fanconia Anemia gene product, and this suggests potential ways the p150 protein may function in Fms signaling.
Animals↗
Germline gain-of-function mutations in SOS1 cause Noonan syndrome.
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation.
Adolescent↗