Disease relevance of HBEGF

• These findings have a high clinical significance, as the downregulation of HBEGF in pre-eclampsia is likely to be a contributing factor leading to the demise of trophoblasts [1].
• Recombinant fusion proteins consisting of mature human HBEGF fused to the plant ribosome-inactivating protein saporin (SAP) were expressed in Escherichia coli [2].
• In addition, the level of HBEGF mRNA declines during the transformation of myometrial SMC into leiomyomas [3].
• We analyzed the expression of HB-EGF in L428, Raji, Jurkat, Karpas 299, L540, 2C8, HL-60, U937, THP-1, ML-3, and K562 cell lines and in primary blasts from 12 acute myeloid leukemia (AML) cases, by reverse-transcriptase polymerase chain reaction (RT-PCR) and Northern blot and by the evaluation of sensitivity to DT [4].
• HB-EGF-PE toxicity was partially mediated by cell surface heparan sulfate proteoglycans (HSPG), since a peptide corresponding to the heparin-binding domain of HB-EGF as well as heparitinase treatment protected the blastocysts from the toxic effects of HB-EGF-PE by about 40% [5].

Psychiatry related information on HBEGF

• Each completed a newly developed measure of distress tolerance (the Distress Tolerance Scale; DTS) and the Eating Disorders Inventory [6].
• RESULTS: The DTS was made up of three scales, each with acceptable psychometric properties [6].
• The DTS is a validated self-rating scale used in the diagnosis of posttraumatic stress disorder (PTSD) [7].

High impact information on HBEGF

• HB-EGF is also expressed in cultured human macrophages and may be involved in macrophage-mediated cellular proliferation [8].
• HBEGF in the complex has the typical EGF-like fold and packs its principal beta hairpin against the face of a beta sheet in the receptor-binding domain of DT [9].
• We describe the crystal structure at 2.65 A resolution of diphtheria toxin (DT) complexed 1:1 with a fragment of its cell-surface receptor, the precursor of heparin-binding epidermal-growth-factor-like growth factor (HBEGF) [9].
• This was achieved by rapidly killing peptide-pulsed DCs carrying a diphtheria toxin receptor transgene with timed injections of diphtheria toxin without altering the course of an accompanying infection [10].
• This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice [11].

Chemical compound and disease context of HBEGF

• Heparin-binding epidermal growth factor-like growth factor/diphtheria toxin receptor expression by acute myeloid leukemia cells [4].
• Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells [12].
• Blockade of the generation of HB-EGF by metalloprotease inhibitors, or abrogation of EGF receptor kinase activity by selective pharmacological inhibitors or antisense oligonucleotides, protects against Ang II-mediated cardiac hypertrophy [13].
• We demonstrate here that lysophosphatidic acid (LPA)-induced ectodomain shedding of heparin-binding EGF-like growth factor (HB-EGF) is a critical to tumor formation in ovarian cancer [14].
• To study the effect of the heparin-binding domain in a chimeric toxin targeted to the EGF receptor, we fused the DNA sequence corresponding to the putative NH2-terminal heparin-binding (HB) domain of HB-EGF to chimeric toxins composed of TGF alpha and two different recombinant forms of Pseudomonas exotoxin (PE) [15].

Biological context of HBEGF

• Our results provide evidence that a post-transcriptional mechanism induced in trophoblasts by low O(2) rapidly amplifies HBEGF signaling to inhibit apoptosis [1].
• At 2% O(2), signaling via HER1 or HER4, known HBEGF receptors, is required for both HBEGF upregulation and protection against apoptosis [1].
• Using a well-characterized human first trimester cytotrophoblast cell line, we found that a 4-hour exposure to 2% O(2) upregulates HBEGF synthesis and secretion independently of an increase in its mRNA [1].
• These data indicate that the GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HBEGF through PKC-dependent activation of metalloprotease(s) in neuronal GT1-7 cells [16].
• AREG was the paralog of HBEGF at human chromosome 5q31 [17].

Anatomical context of HBEGF

• Immunoperoxidase staining showed that HBEGF was a cell-membrane-associated protein in both normal myometrial and leiomyoma SMC with more intense staining in normal myometrium [3].
• SAP alone showed a limited cytotoxic effect on both SMCs and endothelial cells. bFGF had a more potent effect on endothelial cell proliferation than HBEGF. bFGF-SAP was equally cytotoxic for both SMCs and endothelial cells, while HBEGF-SAP had a more selectively cytotoxic effect on SMCs than on endothelial cells [18].
• Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a potent mitogen and chemotactic factor for fibroblasts, smooth muscle cells and keratinocytes [19].
• Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells [20].
• Chinese hamster ovary (CHO) cells genetically engineered to express the human EGF receptor bind with high affinity both EGF and HB-EGF [21].

Associations of HBEGF with chemical compounds

• Heparin-binding epidermal growth factor (HBEGF) binds to EGFRs with high affinity and to heparan sulfate proteoglycans, resulting in increased mitogenic potential compared to other EGF family members [2].
• A construct with a 22-amino-acid flexible linker (L22) between the HBEGF and SAP moieties exhibited an affinity for the EGFR that was comparable to that of HBEGF [2].
• Factors relevant to the biology of leukemic growth, such as tumor necrosis factor-alpha (TNF-alpha), 1alpha,25-(OH)2D3, and especially all-trans retinoic acid (ATRA), upregulated HB-EGF mRNA in HL-60 or ML-3 cells [4].
• It was concluded that HB-EGF TM, which is synthesized exclusively in the luminal epithelium at the site of blastocyst apposition, and which is a juxtacrine adhesion factor for blastocysts, could be one of the mediators of blastocyst adhesion to the uterus in the process of implantation [22].
• Concurrent treatment with HB-EGF and cycloheximide resulted in superinduction of HB-EGF and AR, suggesting that these peptides are immediate early genes in RIE-1 cells [23].

Physical interactions of HBEGF

• Uterine extracts also contained an EGF-R-binding factor that was eluted from heparin by 1.0 M NaCl and was antagonized by HB-EGF antiserum [24].
• Heparin-like molecules on the cell surface potentiate binding of diphtheria toxin to the diphtheria toxin receptor/membrane-anchored heparin-binding epidermal growth factor-like growth factor [25].
• BAG-1 is a novel cytoplasmic binding partner of the membrane form of heparin-binding EGF-like growth factor: a unique role for proHB-EGF in cell survival regulation [26].
• Endothelial-derived heparin binding EGF-like growth factor (HB-EGF) was shown to mediate this process by signaling via ErbB1 and ErbB2 receptors in SMCs [27].
• CD9 antigen interacts with heparin-binding EGF-like growth factor through its heparin-binding domain [28].

Co-localisations of HBEGF

• In epiretinal membranes of patients with PVR, HB-EGF immunoreactivity partially colocalized with GFAP [29].
• HB-EGF colocalized with HER-1 and HER-4 in HPMCs and induced their adhesion to collagen type I, expression of beta 1 integrins, and migration [30].

Regulatory relationships of HBEGF

• Signal transduction by the EGF receptor tyrosine kinase as evidenced by receptor autophosphorylation is induced by HB-EGF only in the presence of heparin, in contrast to EGF-induced receptor autophosphorylation, which is independent of heparin [21].
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) induced HB-EGF mRNA and acquisition of sensitivity to DT in one previously HB-EGF-negative leukemia case [4].
• In addition, because effects of BAG-1 on regulated secretion of soluble HB-EGF were also identified, this interaction has the potential to alter the signaling capabilities of both the membrane-anchored and the diffusible forms of the growth factor [26].
• Heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein expression is induced by EGF in MCF-10A nontransformed and Ha-ras transfected human mammary epithelial cells [31].
• The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists [32].

Other interactions of HBEGF

• Interestingly, DT-induced 22Na+ influx was weak in DTR-EGFR cells and not detectable in DTR-GPI cells [33].
• Co-immunoprecipitation of DRAP27/CD9 with DTR and chemical cross-linking suggest a tight association of these membrane-bound proteins [34].
• Our findings suggest that HB-EGF is relatively abundant in human gastric cancers and that co-expression of the EGF ligand family may lead to excessive activation of EGF-R in this disorder [35].
• ADAM19 colocalized with tubular and interstitial NRG, however, not with HB-EGF [36].
• There have been no reports on the HB-EGF, BTC and EPR expression in mesenchymal malignancies of fibrohistiocytic origin including malignant fibrous histiocytoma (MFH) [37].

Analytical, diagnostic and therapeutic context of HBEGF

• HB-EGF messenger RNA and protein were determined with Northern and Western blotting, respectively [38].
• Structure-function analysis of the diphtheria toxin receptor toxin binding site by site-directed mutagenesis [39].
• HB-EGF was purified from the conditioned medium of U-937 cells using cation exchange, copper affinity, heparin affinity, and two rounds of C4 reversed phase liquid chromatography [40].
• By Northern blot analysis, there was a 4.7-fold increase in HB-EGF mRNA levels in human gastric cancers compared with normal gastric tissues [35].
• Cloning of the nested PCR product revealed a 380-bp porcine HB-EGF cDNA sequence that was 78-85% homologous to primate or rodent HB-EGF [24].

References