Epithelial Inflammation Resulting from an Inherited Loss-of-Function Mutation in EGFR

Campbell, Patrick; Morton, Penny E.; Takeichi, Takuya; Salam, Amr; Roberts, Nerys; Proudfoot, Laura E.; Mellerio, Jemima E.; Aminu, Kingi; Wellington, Cheryl L.; Patil, Sachin; Akiyama, Masashi; Liu, Lu; McMillan, James R.; Aristodemou, Sophia; Ishida‐Yamamoto, Akemi; Abdul‐Wahab, Alya; Petrof, Gabriela; Fong, Kenneth; Harnchoowong, Sarawin; Stone, Kristina; Harper, John; McLean, William; Simpson, Michael A.; Parsons, Maddy; McGrath, John A.

doi:10.1038/jid.2014.164

Cited by 82 publications

(82 citation statements)

References 34 publications

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“…Mice lacking ADAM17 resemble mice with defects in EGFR signaling in that they have open eyes at birth, enlarged semilunar heart valves, and enlarged hypertrophic zones in long bone growth plates, most likely caused by a lack of ADAM17-dependent release of the EGFR ligands transforming growth factor α (TGF-α) and heparin-binding epidermal growth factor (HB-EGF) (3,(6)(7)(8)(9)(10)(11)(12)(13)(14). In humans, defects in skin and intestinal barrier protection have been reported in a patient lacking ADAM17 (15) and in patients treated with EGFR inhibitors (16,17), and similar skin defects were recently identified in a patient with defective EGFR signaling (18). Mouse models of ADAM17/EGFR signaling appear to recapitulate these mechanisms, because defects in skin barrier protection can be observed by inactivating either ADAM17 or the EGFR in keratinocytes (19), as well as in mice expressing very low levels of ADAM17, which also have increased susceptibility to intestinal inflammation (20).…”

mentioning

confidence: 93%

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Li¹,

Maretzky²,

Weskamp³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

208

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The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17 −/− mice die perinatally with open eyes, like Egfr −/− mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2 −/− mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2 −/− double knockout mice resemble Adam17 −/− and Egfr −/− mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2 −/− tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFRdependent pathologies.inactive Rhomboid proteins | a disintegrin and metalloprotease 17 | epidermal growth factor receptor | heparin-binding epidermal growth factor | transforming growth factor alpha

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mentioning

confidence: 93%

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Li¹,

Maretzky²,

Weskamp³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

134

208

View full text Add to dashboard Cite

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“…Although fewer data are available, a similar scenario seems to apply also to HNC. Indeed, a strict cross-talk between inflammatory cytokines and EGFR signaling to foster tissue regeneration has been repeatedly reported for epithelial tissues in general (26), and for squamous epithelia in particular (27)(28)(29).…”

mentioning

confidence: 88%

Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies

Bertotti

Sassi

2015

Clinical Cancer Research

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Monoclonal antibodies targeting the EGF receptor (EGFR) tyrosine kinase, such as cetuximab and panitumumab, achieve clinically meaningful responses in patients affected by head and neck and colorectal cancers. Despite this evidence of efficacy, no genomic abnormalities that robustly predict sensitivity to EGFR blockade have been yet identified. This suggests that, in some tumor contexts, EGFR dependency is not acquired during neoplastic transformation and rather reflects an aberrant declination of physiologic traits typical of normal tissue counterparts. Indeed, EGFR signals are crucial for the reconstitution of damaged mucosa in the context of acute inflammation, and their sustained activation is likely to turn into a pro-oncogenic cue during chronic inflammation. Although positive predictors of response to anti-EGFR antibodies remain unknown, multiple determinants of resistance have been described, including alterations interfering with antibody-receptor interaction, deregulation of parallel signaling pathways, and mutations in downstream transducers. These findings provide new opportunities for the optimization of therapeutic strategies based on drug combinations. However, the emerging notion that genetic interactions and compensatory mechanisms may affect-both positively and negatively-the efficacy of targeted therapies complicates the rational design of combinatorial approaches and implies a rethinking of the criteria required to prioritize laboratory findings for clinical validation in investigational trials. Clin Cancer Res; 21(15); 3377-83. Ó2015 AACR.

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“…EGFR can inhibit IRF1 activation, resulting in suppression of the IFN pathway and ISG synthesis, especially IFNκ 270,419–421 . Therapeutic inhibition of EGFR in humans consequently results in widespread inflammatory side effects, especially in the skin 417,418,422 . IFN inhibition can abolish the therapeutic effect of anti-EGFR therapies 423 (reviewed in 424 ), suggesting some anti- growth factor therapies may depend on IFN responses.…”

Section: Immune Interactionsmentioning

confidence: 99%

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Woodby

Scott

Bodily

2016

Progress in Molecular Biology and Translational Science

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Human papillomaviruses (HPV) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection.

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Epithelial Inflammation Resulting from an Inherited Loss-of-Function Mutation in EGFR

Cited by 82 publications

References 34 publications

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Molecular Pathways: Sensitivity and Resistance to Anti-EGFR Antibodies

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

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