Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiopoietin-1 (ANGPT1), Angiopoietin-4 (ANGPT4), VEGF, FGF2, FGF4, HGF, Ephrin, IL8 and CXCL12 (SFD1) are pro-angiogenic factors (angiogenic activators), while Angiopoietin-2 (ANGPT2), Angiostatin, Endostatin, Tumstatin, Canstatin, THBS1, THBS2, TNFSF15 (VEGI) and Vasohibin (VASH1) are anti-angiogenic factors (angiogenic inhibitors). ANGPT1 and ANGPT2 are ligands for TIE family receptor tyrosine kinases, TIE1 and TIE2 (TEK). Angiopoietin family consists of ANGPT1, ANGPT2, ANGPT4, ANGPTL1 (ANGPT3), ANGPTL2, ANGPTL3 (ANGPT5), ANGPTL4, ANGPTL5, ANGPTL6 and ANGPTL7. TCF/LEF binding sites within the promoter region of human Angiopoietin family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the human ANGPTL7 promoter, comparative genomics analyses on ANGPTL7 orthologs were further performed. ANGPTL7 gene at human chromosome 1p36.22 was located within intron 28 of FRAP1 gene encoding mTOR protein. Chimpanzee ANGPTL7 gene, consisting of five exons, was located within NW_101546.1 genome sequence. Chimpanzee ANGPTL7 showed 99.4% and 86.1% total-amino-acid identity with human ANGPTL7 and mouse Angptl7, respectively. Human ANGPTL7 mRNA was expressed in neural tissues, keratoconus cornea, trabecular meshwork, melanotic melanoma and uterus endometrial cancer, while mouse Angptl7 mRNA was expressed in four-cell embryo, synovial fibroblasts, thymus, uterus and testis. Four TCF/LEF-binding sites within human ANGPTL7 promoter were conserved in chimpanzee ANGPTL7 promoter; however, only an unrelated TCF/LEF-binding site occurred in mouse and rat Angptl7 promoters. Human ANGPTL7, characterized as potent target gene of WNT/ beta-catenin signaling pathway, is a pharmacogenomics target in the fields of oncology and regenerative medicine.
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PMID:Comparative integromics on Angiopoietin family members. 1668 28

The forkhead C1 (FOXC1) transcription factor is involved in the development and regulation of several organs, including the eye, where FOXC1 alterations cause iris, trabecular meshwork and corneal anomalies. Using nickel agarose chromatin enrichment with human anterior segment cells, we previously identified the fibroblast growth factor 19 (FGF19) locus as a gene potentially regulated by FOXC1. Here, we demonstrate that FGF19 is a direct target of FOXC1 in the eye. FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells in cell culture and in zebrafish embryos. Through the FGFR4 tyrosine kinase, FGF19 promotes MAPK phosphorylation in the developing and mature cornea. During development, loss of either FOXC1 or FGF19 results in complementary, but distinct, anterior segment dysgeneses. This study reveals an important role for FOXC1 in the direct regulation of the FGF19-FGFR4-MAPK pathway to promote both the development and maintenance of anterior segment structures within the eye.
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PMID:FGF19 is a target for FOXC1 regulation in ciliary body-derived cells. 1700 Jul 8

The interaction of vascular endothelial growth factor (VEGF) and its receptors (Flt-1, Flk-1/KDR) is correlated with neovascularization in the eyes. Therefore, blocking the binding of VEGF and the corresponding receptor has become critical for inhibiting corneal neovascularization. In this study, we have expressed the cDNA for sFlk-1 under the control of cytomegalovirus immediate-early promoter (CMV) from an E1/partial E3 deleted replication defective recombinant adenovirus, and Ad.sflk-1 expression was determined by Western blotting. We have shown that conditioned media from Ad.sflk-1-infected ARPE-19 cells significantly reduced VEGF-induced human umbilical vein endothelial cells (HUVEC) and murine endothelial cells (SVEC) proliferation in vitro compared with the control vector. In vivo, adenoviral vectors expressing green fluorescent protein alone (Ad.GFP) were utilized to monitor gene transfer to the cornea. Moreover, in the models of corneal neovascularization, the injection of Ad.sflk-1 (10(8)PFU) into the anterior chamber could significantly inhibit angiogenic changes compared with Ad.null-injected and vehicle-injected models. Immunohistochemical analysis showed that corneal endothelial cells and corneal stroma of cauterized rat eyes were efficiently transduced and expressed sFlk-1. These results not only support that adenoviral vectors are capable of high-level transgene expression but also demonstrate that Ad.sflk-1 gene therapy might be a feasible approach for inhibiting the development of corneal neovascularization.
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PMID:Inhibition of corneal neovascularization by recombinant adenovirus-mediated sFlk-1 expression. 1769 88

We used loss-of-function analysis to determine the role of fibroblast growth factor receptor 2 (FGFR2) in telencephalic progenitors, and also to examine interactions between FGFR and Notch signaling. While the telencephalon of FGFR2 mutants appears grossly normal, mutant telencephalic progenitors exhibit altered proliferative behavior in vivo and in vitro. Based upon our prior finding that Notch1 activation increased neurosphere frequency in FGF2, we tested whether this effect is mediated by FGFR1 or FGFR2. We found that Notch1 activation increased neurosphere frequency in cells mutant for either FGFR1 or FGFR2, but had no effect on the reduced size of neurospheres mutant for those receptors. Additional analyses revealed biochemical changes in the adult neocortex mutant for the IIIc isoform of FGFR2, and essential roles for FGFR2 in nasopharynx, eyelid, and cornea development.
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PMID:Fibroblast growth factor receptor 2 plays an essential role in telencephalic progenitors. 1807 59

Lumican is a major proteoglycans of the human cornea. Lumican knock-out mice have been shown to lose corneal transparency and to display delayed wound healing. The purpose of this study was to define the role of lumican in corneal epithelial cell migration. Over-expression of lumican in human corneal epithelial (HCE-T) cells increased both cell migration and proliferation, and increased levels of integrins alpha2 and beta1. ERK 1/2 was also activated in lumican over-expressed cells. When we treated HCE-T cells with the ERK-specific inhibitor U0126, cell migration and the expression of integrin beta1 were completely blocked. These data provide evidence that lumican stimulates cell migration in the corneal epithelium by activating ERK 1/2, and point to a novel signaling pathway implicated in corneal epithelial cell migration.
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PMID:Lumican induces human corneal epithelial cell migration and integrin expression via ERK 1/2 signaling. 1847 77

Since approval of the use of the excimer laser in 1995 to reshape the cornea, significant developments in the correction of refractive errors such as myopia, hyperopia, and astigmatism have been achieved. Combined with other advanced ophthalmological instruments (e.g. anterior segment imaging systems, the femtosecond laser, wavefront-guided customized ablation) and the knowledge accumulated concerning the basic science of refractive errors (e.g. biomechanics and wound healing of the cornea, higher-order aberrations), laser refractive surgery has promisingly outshone other conventional techniques (e.g. radial keratotomy [RK], automated lamellar keratectomy [ALK]) in terms of both safety and efficacy. Photorefractive keratectomy (PRK) produces stable and predictable results with a safe profile. Similarly, laser in situ keratomileusis (LASIK) is also safe and efficacious with the additional advantages of rapid visual recovery and minimal postoperative pain. The choice between the two methods is made only after thoughtful discussion between the surgeon and the patient. Despite these advances, certain limitations and complications do exist. There are also specific and controversial circumstances for which studies should be conducted to make further breakthroughs and avoid annoying complications. In this review, the basic knowledge, surgical issues, and clinical outcomes, of laser refractive surgery, as well as complex cases, will be presented.
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PMID:Overview of laser refractive surgery. 1878 46

Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arteriogenic factors. Using in vivo angiogenesis and ischemic hind-limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF-2) in combinations with PDGF-AA and PDGF-AB, two members of the platelet-derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF-AA/FGF-2 and PDGF-AB/FGF-2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF-2 up-regulates PDGFR-alpha and -beta expression levels in the newly formed blood vessels. Interestingly, PDGF-AB/FGF-2, but not PDGF-AA/FGF-2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti-PDGFR-beta neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability. These findings demonstrate that PDGFR-beta receptor is essential for vascular stability. Similarly, PDGF-AB/FGF-2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF-AB/FGF-2 leads to dramatic improvement of the paw's skin perfusion. Immunohistochemical analysis of the treated skeletal muscles confirms that a combination of PDGF-AB and FGF-2 significantly induces arteriogenesis in the ischemic tissue. A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases.
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PMID:Differential roles of PDGFR-alpha and PDGFR-beta in angiogenesis and vessel stability. 1882 23

ASK1-interacting protein-1 (AIP1), a recently identified member of the Ras GTPase-activating protein family, is highly expressed in vascular ECs and regulates EC apoptosis in vitro. However, its function in vivo has not been established. To study this, we generated AIP1-deficient mice (KO mice). Although these mice showed no obvious defects in vascular development, they exhibited dramatically enhanced angiogenesis in 2 models of inflammatory angiogenesis. In one of these models, the enhanced angiogenesis observed in the KO mice was associated with increased VEGF-VEGFR2 signaling. Consistent with this, VEGF-induced ear, cornea, and retina neovascularization were greatly augmented in KO mice and the enhanced retinal angiogenesis was markedly diminished by overexpression of AIP1. In vitro, VEGF-induced EC migration was inhibited by AIP1 overexpression, whereas it was augmented by both AIP1 knockout and knockdown, with the enhanced EC migration caused by AIP1 knockdown being associated with increased VEGFR2 signaling. We present mechanistic data that suggest AIP1 is recruited to the VEGFR2-PI3K complex, binding to both VEGFR2 and PI3K p85, at a late phase of the VEGF response, and that this leads to inhibition of VEGFR2 signaling. Taken together, our data demonstrate that AIP1 functions as an endogenous inhibitor in VEGFR2-mediated adaptive angiogenesis in mice.
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PMID:AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and inflammatory angiogenesis in mice. 1903 61

Myofibroblast development and haze generation in the corneal stroma is mediated by cytokines, including transforming growth factor-beta (TGF-beta), and possibly other cytokines. This study examined the effects of stromal PDGF-beta blockade on the development of myofibroblasts in response to -9.0 diopter photorefractive keratectomy in the rabbit. Rabbits that had haze generating photorefractive keratectomy (PRK, for 9 diopters of myopia) in one eye were divided into three different groups: stromal application of plasmid pCMV.PDGFRB.23KDEL expressing a subunit of PDGF receptor b (domains 2-3, which bind PDGF-B), stromal application of empty plasmid pCMV, or stromal application of balanced salt solution (BSS). The plasmids (at a concentration 1000ng/microl) or BSS was applied to the exposed stroma immediately after surgery and every 24h for 4-5 days until the epithelium healed. The group treated with pCMV.PDGFRB.23KDEL showed lower alphaSMA+ myofibroblast density in the anterior stroma compared to either control group (P<or=0.001). Although there was also lower corneal haze at the slit lamp at one month after surgery, the difference in haze after PDGF-B blockade was not statistically significant compared to either control group. Stromal PDGF-B blockade during the early postoperative period following PRK decreases stromal alphaSMA+ myofibroblast generation. PDGF is an important modulator of myofibroblast development in the cornea.
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PMID:Corneal stroma PDGF blockade and myofibroblast development. 1913 60

Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-alpha-converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of gamma-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors.
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PMID:Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells. 1927 74


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