Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

Miyamoto, Shingo; Yagi, Hiroshi; Yotsumoto, Fusanori; Kawarabayashi, Tatsuhiko; Mekada, Eisuke

doi:10.1111/j.1349-7006.2006.00188.x

Cited by 135 publications

(135 citation statements)

References 72 publications

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“…The expression of EGFR ligands is relevant to the malignant phenotype of cancers that express wild-type ligand-responsive EGFRs. Among the cognate ligands for EGFR, transforming growth factor-a (TGF-a) and heparin-binding epidermal growth factor -like (HB-EGF) growth factor have been most strongly implicated in oncogenesis (8,9). Cell biological, in vitro and in vivo transgenic, clinical correlative, and therapeutic evidence point to a role for EGFR and its downstream cell signaling pathways, such as phosphoinositide 3-kinase/Akt and Ras/mitogen-activated protein kinase (MAPK) in the generation and malignant progression in various cancer subsets, including the astroglial malignancies (10).…”

Section: Introductionmentioning

confidence: 99%

Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

Reznik

Sang

et al. 2008

Molecular Cancer Research

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The mechanisms and biological implications of coordinated receptor tyrosine kinase coactivation remain poorly appreciated. Epidermal growth factor receptor (EGFR) and c-Met are frequently coexpressed in cancers, including those associated with hepatocyte growth factor (HGF) overexpression, such as malignant astrocytoma. In a previous analysis of the HGF-induced transcriptome, we found that two EGFR agonists, transforming growth factor-A and heparin-binding epidermal growth factor -like growth factor (HB-EGF), are prominently up-regulated by HGF in human glioma cells. We now report that stimulating human glioblastoma cells with recombinant HGF induces biologically relevant EGFR activation. EGFR phosphorylation at Tyr 845 and Tyr 1068 increased 6 to 24 h after cell stimulation with HGF and temporally coincided with the induction of transforming growth factor-A (f5-fold) and HB-EGF (f23-fold) expression. Tyr 845 and Tyr 1068 phosphorylation, in response to HGF, was inhibited by cycloheximide and actinomycin D, consistent with a requirement for DNA transcription and RNA translation. Specifically, blocking HB-EGF binding to EGFR with the antagonist CRM197 inhibited HGF-induced EGFR phosphorylation by 60% to 80% and inhibited HGF-induced S-G 2 -M transition. CRM197 also inhibited HGF-induced anchorage-dependent cell proliferation but had no effect on HGF-mediated cytoprotection. These findings establish that EGFR can be activated with functional consequences by HGF as a result of EGFR ligand expression. This transcription-dependent cross-talk between the HGF receptor c-Met and EGFR expands our understanding of receptor tyrosine kinase signaling networks and may have considerable consequences for oncogenic mechanisms and cancer therapeutics.

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Section: Introductionmentioning

confidence: 99%

Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

Reznik

Sang

et al. 2008

Molecular Cancer Research

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“…Upon membrane insertion and signal peptide cleavage, pro-HB-EGF is synthesized as a type 1 transmembrane protein that is trafficked to the plasma membrane and proteolytically shed by matrix metalloprotease to release the biologically active soluble HB-EGF (13)(14). In addition, shedding of pro-HB-EGF also provides an important molecular link between GPCR activation and EGF receptor transactivation (15).…”

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confidence: 99%

Requirement of an Intermediate Gene Expression for Biphasic ERK1/2 Activation in Thrombin-stimulated Vascular Smooth Muscle Cells

Sastre

Großmann

Reusch

et al. 2008

Journal of Biological Chemistry

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The expression of contractile proteins in vascular smooth muscle cells is controlled by still poorly defined mechanisms. A thrombin-inducible expression of smooth muscle-specific ␣-actin and myosin heavy chain requires transactivation of the epidermal growth factor (EGF) receptor and a biphasic activation of ERK1/2. Here we demonstrate that the sustained second phase of ERK1/2 phosphorylation requires de novo RNA and protein synthesis. Depolymerization of the actin cytoskeleton by cytochalasin D or disruption of transit between the endoplasmic reticulum and the Golgi apparatus by brefeldin A prevented the second phase of ERK1/2 phosphorylation. We thus conclude that synthesis and trafficking of a plasma membrane-resident protein may be critical intermediates. The principal function of vascular smooth muscle (VSM) 2 cells in a developed vascular system is the regulation of blood pressure and flow. In certain diseased states, however, VSM cells can undergo a phenotypic modulation toward a proliferative and secretory phenotype or by reverting toward the nonproliferative contractile phenotype (1). The transition from a differentiated phenotype to a fibroblast-like proliferative state is observed during the onset or progression of atherosclerosis (2-3), one of the most common diseases in developed countries (4 -5). Under these conditions, the VSM cell phenotype is reminiscent of that observed during vascular development, where VSM cells play a key role in morphogenesis of the blood vessel and exhibit a high proliferative index, migrate, and produce extracellular matrix components (6). Conditions that promote the proliferative phenotype include the combined action of growth factors, proteolytic enzymes, and exposure to extracellular matrix proteins (7).The reciprocal process has been observed upon completion of wound healing or during formation and organization of a fibrous cap. Under these conditions, VSM cells are exposed to various stimuli, including macrophage-and lymphocyte-derived cytokines and serum components that are currently being discussed as critical regulators of plaque stability.On the molecular level, phenotypic modulation of VSM cells depends on the activation of mitogen-activated protein (MAP) kinases (8). The epidermal growth factor (EGF) receptor is transactivated after G protein-coupled receptor (GPCR) activation and recruits the guanine nucleotide exchange factor (Sos) through adaptor proteins, Shc and Grb2, thereby initiating the canonical Ras/Raf/MEK/ERK cascade (9 -10). Activated MAP kinases of the extracellular signal-regulated kinase (ERK1/2) family in turn translocate to the nucleus and phosphorylate nuclear transcription factors or transcriptional coactivators (11).Within the family of EGF receptor ligands, heparin-binding EGF (HB-EGF) has been implicated in vascular remodeling because it is a potent mitogen, acts as a chemotactic factor for VSM cells, and is abundantly expressed in vascular lesions such as atherosclerosis (12). Upon membrane insertion and signal peptide cleavage, pro-HB-E...

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“…It is possible that on the one hand ox-PAPC leads to IL-8 induction and promotes early phase of angiogenesis, while on the other hand it simultaneously down-regulates the IL-15 gene expression and inhibits maturation of the capillary network. Such a pathological mechanism might result in generation of non-functional, breakable capillaries; which typically characterize unstable atherosclerotic plaques or tumor vasculature [11].…”

Section: Discussionmentioning

confidence: 99%

Modulation of endothelial cell proliferation and capillary network formation by the ox-LDL component: 1-palmitoyl-2-archidonoyl-sn-glycero-3-phosphocholine (ox-PAPC)

et al. 2011

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Atherosclerotic plaque formation is often associated with pathological angiogenesis. Modified phospholipids, including oxidized lipoproteins such as LDL, are found to induce adhesion of the monocytes to the endothelial cells and to stimulate their chemotaxis. Effects of oxidized 1-palmitoyl-2-archidonoyl-sn-glycero-3-phosphocholine (ox-PAPC) mimic actions of minimally modified LDL in vivo. Interleukin-8 (IL-8) and interleukin-15 (IL-15) are known to induce both inflammation and angiogenesis. The goal of our study was to analyze a potential synergism between ox-PAPC and IL-15 in the in vitro model of angiogenesis carried out in the human endothelial cells (HUVECs). Increasing IL-15 concentrations led to formation of the tube-like structures in the matrigel 3D-model of angiogenesis (P \ 0.05), in contrast to ox-PAPC that inhibited this process. HUVECs incubation with ox-PAPC led to reduced IL-15 gene basal expression (P = 0.033) along with parallel increase, however statistically insignificant, of basal gene expression of IL-8 (P = 0.086). Our findings point to the ox-PAPC opposite effects on the IL-8-and IL-15-mediated angiogenic responses that contribute to pathological angiogenesis induced by ox-LDL.

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Heparin‐binding epidermal growth factor‐like growth factor as a novel targeting molecule for cancer therapy

Abstract: HB-EGF, a member of the EGF family of growth factors, exerts its

Cited by 135 publications

References 72 publications

Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

Transcription-Dependent Epidermal Growth Factor Receptor Activation by Hepatocyte Growth Factor

Requirement of an Intermediate Gene Expression for Biphasic ERK1/2 Activation in Thrombin-stimulated Vascular Smooth Muscle Cells

Modulation of endothelial cell proliferation and capillary network formation by the ox-LDL component: 1-palmitoyl-2-archidonoyl-sn-glycero-3-phosphocholine (ox-PAPC)

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