Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.

Cook, Paul W.; Piepkorn, Michael; Clegg, Christopher H.; Plowman, Gregory D.; Demay, Justine; Brown, Jeffrey R.; Pittelkow, Mark R.

doi:10.1172/jci119766

Cited by 203 publications

(189 citation statements)

References 51 publications

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“…The phenotype of the LRIG1 knockout mouse, a psoriatic-like epidermal hyperplasia, supports its role as a growth suppressor and negative regulator of EGFR signaling because transgenic mice overexpressing EGFR ligands (Cook et al, 1997;Vassar and Fuchs, 1991) display a phenotype similar to LRIG1 À/À mice. Interestingly, loss of a distinct negative regulator of ErbB receptors, Mig6/RALT, also manifests in an epidermal hyperplasia, indicating that the skin is a sensitive reporter of ErbB oversignaling (Ferby et al, 2006).…”

Section: Discussionmentioning

confidence: 87%

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

et al. 2008

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Epidermal growth factor receptor (EGFR) mutation is frequently observed in human cancer and contributes to the growth, survival and therapeutic resistance of tumors. EGFRvIII is an oncogenic EGFR mutant resulting from the deletion of exons 2-7 and is the most common EGFR mutant observed in glioblastoma multiforme, an aggressive brain tumor. EGFRvIII is constitutively active but poorly ubiquitinated, leading to inefficient receptor trafficking to lysosomes and unattenuated oncogenic signaling. The mechanism by which EGFRvIII evades downregulation is not fully understood although recent studies suggest that its interaction with the ubiquitin ligase Cbl may be compromised. In this study, we examine the regulation of EGFRvIII by the recently identified negative regulator, LRIG1, which targets EGFR through recognition of its extracellular domain. Here, we determine whether the extracellular domain deletion in EGFRvIII renders it refractory to LRIG1 regulation. We find that EGFRvIII retains interaction with LRIG1 and is in fact more sensitive to LRIG1 action than wild-type receptor. We demonstrate that LRIG1 regulation of EGFRvIII is distinct from the only other known mechanism of EGFR regulation, Cbl-mediated degradation. Ectopic expression of LRIG1 in EGFRvIII( þ ) glioblastoma cells opposes EGFRvIII-driven tumor cell proliferation, survival, motility and invasion. Finally, RNAi-mediated silencing of LRIG1 alters EGFRvIII intracellular trafficking and leads to enhanced EGFRvIII expression, suggesting that loss of LRIG1 in tumors may contribute to a permissive environment for EGFRvIII overexpression, contributing to EGFRvIII oncogenesis.

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Section: Discussionmentioning

confidence: 87%

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

et al. 2008

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“…Both amphiregulin and HB-EGF bind to EGFR, have been determined to be the primary growth factors driving autocrine KC proliferation (9), and are overexpressed by KCs in psoriatic lesions (61). The potential role of amphiregulin in psoriasis and psoriatic arthritis has also been supported by preclinical animal studies (59,63,64).…”

Section: Discussionmentioning

confidence: 98%

The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

Susan

Valdez²,

Wu³

et al. 2007

The Journal of Immunology

445

256

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IL-19, IL-20, IL-22, IL-24, and IL-26 are members of the IL-10 family of cytokines that have been shown to be up-regulated in psoriatic skin. Contrary to IL-10, these cytokines signal using receptor complex R1 subunits that are preferentially expressed on cells of epithelial origin; thus, we henceforth refer to them as the IL-20 subfamily cytokines. In this study, we show that primary human keratinocytes (KCs) express receptors for these cytokines and that IL-19, IL-20, IL-22, and IL-24 induce acanthosis in reconstituted human epidermis (RHE) in a dose-dependent manner. These cytokines also induce expression of the psoriasisassociated protein S100A7 and keratin 16 in RHE and cause persistent activation of Stat3 with nuclear localization. IL-22 had the most pronounced effects on KC proliferation and on the differentiation of KCs in RHE, inducing a decrease in the granular cell layer (hypogranulosis). Furthermore, gene expression analysis performed on cultured RHE treated with these cytokines showed that IL-19, IL-20, IL-22, and IL-24 regulate many of these same genes to variable degrees, inducing a gene expression profile consistent with inflammatory responses, wound healing re-epithelialization, and altered differentiation. Many of these genes have also been found to be up-regulated in psoriatic skin, including several chemokines, ␤-defensins, S100 family proteins, and kallikreins. These results confirm that IL-20 subfamily cytokines are important regulators of epidermal KC biology with potentially pivotal roles in the immunopathology of psoriasis.

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“…Scale bars: 60 μm. severely affected regions (Cook et al, 1997). Targeting of KGF overexpression in mouse epidermis also resulted in a marked suppression of HF morphogenesis (Guo et al, 1993).…”

Section: Inhibition Of Placodes By Egfr and Fgfr2(iiib)mentioning

confidence: 99%

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

et al. 2009

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A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

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Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype.

Cited by 203 publications

References 51 publications

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

LRIG1 negatively regulates the oncogenic EGF receptor mutant EGFRvIII

The Effects of IL-20 Subfamily Cytokines on Reconstituted Human Epidermis Suggest Potential Roles in Cutaneous Innate Defense and Pathogenic Adaptive Immunity in Psoriasis

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

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