大肠癌组织中表皮生长因子及受体的检测

本文应用免疫组化ABC法检测52例大肠癌和18例正常结肠组织中表皮生长因子（EGF）和表皮生长因子受体（EGF－R）的表达状况。正常组织中EGF阳性率22．2％，EGF－R阳性率16．7％，大肠癌EGF阳性率67．3％，EGF－R阳性率61．5％，二者均明显高于正常对照组织，（P＜0．05）。EGF和EGF－R阳性率与患者年龄，性别及肿瘤部位无明显相关，但随着肿瘤浸润度的加深，EGF与EGF－R的阳性率逐渐增高，有淋巴结转移者二者阳性率高于淋转阴性者，特别是EGF与EGF－R双阳者中有82．6％为进展期大肠癌，另发现低分化大肠癌中EGF和EGF－R阳性率明显低于中高分化癌。本文结果提示：部分大肠癌存在EGF或EGF－R的过度表达；EGF与EGF－R的过度表达与肿瘤润度及淋巴转移有关，其检测可作为诊断肿瘤恶性程度的一项辅助指标，部分正常大肠粘膜组织中也有少量EGF或EGF－R表达。     

Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3

The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a member of the EGF receptor (EGFR) family, lacks several residues that are critical for catalysis. Because catalytic activity in EGFR family members is switched on by an allosteric interaction between kinase domains in an asymmetric kinase domain dimer, HER3 might be specialized to serve as an activator of other EGFR family members. We have determined the crystal structure of the HER3 kinase domain and show that it appears to be locked into an inactive conformation that resembles that of EGFR and HER4. Although the crystal structure shows that the HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed by inactive HER4 kinase domains in crystal structures determined previously, and molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are stable. The kinase domains of HER3 and HER4 form similar chains in their respective crystal lattices, in which N-lobe dimers are linked together by reciprocal exchange of C-terminal tails. The conservation of this tiling pattern in HER3 and HER4, which is the closest evolutionary homolog of HER3, might represent a general mechanism by which this branch of the HER receptors restricts ligand-independent formation of active heterodimers with other members of the EGFR family.     

Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways

Ectodomain cleavage of cell-surface proteins by A disintegrin and metalloproteinases (ADAMs) is highly regulated, and its dysregulation has been linked to many diseases. ADAM10 and ADAM17 cleave most disease-relevant substrates. Broad-spectrum metalloprotease inhibitors have failed clinically, and targeting the cleavage of a specific substrate has remained impossible. It is therefore necessary to identify signaling intermediates that determine substrate specificity of cleavage. We show here that phorbol ester or angiotensin II-induced proteolytic release of EGF family members may not require a significant increase in ADAM17 protease activity. Rather, inducers activate a signaling pathway using PKC-α and the PKC-regulated protein phosphatase 1 inhibitor 14D that is required for ADAM17 cleavage of TGF-α, heparin-binding EGF, and amphiregulin. A second pathway involving PKC-δ is required for neuregulin (NRG) cleavage, and, indeed, PKC-δ phosphorylation of serine 286 in the NRG cytosolic domain is essential for induced NRG cleavage. Thus, signaling-mediated substrate selection is clearly distinct from regulation of enzyme activity, an important mechanism that offers itself for application in disease.     

Mutant EGFR is required for maintenance of glioma growth in vivo,and its ablation leads to escape from receptor dependence

Epidermal growth factor receptor (EGFR) gene amplification is the most common genetic alteration in high-grade glioma, and ≈50% of EGFR-amplified tumors also harbor a constitutively active mutant form of the receptor, ΔEGFR. Although ΔEGFR greatly enhances tumor growth and is thus an attractive target for anti-glioma therapies, recent clinical experiences with EGFR kinase inhibitors have been disappointing, because resistance is common and tumors eventually recur. Interestingly, it has not been established whether ΔEGFR is required for maintenance of glioma growth in vivo, and, by extension, if it truly represents a rational therapeutic target. Here, we demonstrate that in vivo silencing of regulatable ΔEGFR with doxycycline attenuates glioma growth and, therefore, that it is crucial for maintenance of enhanced tumorigenicity. Similar to the clinical experience, tumors eventually regained aggressive growth after a period of stasis, but interestingly, without re-expression of ΔEGFR. To determine how tumors acquired this ability, we found that a unique gene, KLHDC8, herein referred to as SΔE (Substitute for ΔEGFR Expression)-1, is highly expressed in these tumors, which have escaped dependence on ΔEGFR. SΔE-1 is also expressed in human gliomas and knockdown of its expression in ΔEGFR-independent “escaper” tumors suppressed tumor growth. Taken together, we conclude that ΔEGFR is required for both glioma establishment and maintenance, and that gliomas undergo selective pressure in vivo to employ alternative compensatory pathways to maintain aggressiveness in the event of EGFR silencing. Such alternative pathways function as substitutes for ΔEGFR signaling and should therefore be considered as potential targets for additional therapy.     

表皮生长因子受体在胶质瘤中的表达变化及其在细胞信号传导中的作用

目的观察胶质瘤组织及细胞U251中表皮生长因子受体（EGFR）的表达变化,探讨其在细胞信号传导通路中的作用。方法采用免疫组化SP法检测78例脑胶质瘤组织和U251中的EGFR。用EGF作用U251,MTT法检测U251细胞增殖情况,Western blot法检测U251中磷酸化EGFR（p-EGFR）。结果 78例胶质瘤组织中EGFR阳性表达率为66.67%（52/78）,且与胶质瘤的病理分级呈正相关（r=0.441,P〈0.05）。EGF作用后,U251细胞增殖显著、U251中p-EGFR水平明显提高（P均〈0.05）。结论胶质瘤组织、细胞中EGFR均呈过度表达。EGFR通过其介导的细胞信号传导通路促进细胞增殖,EGFR在细胞信号传导通路中发挥重要作用。     

健中愈疡片对乙酸诱导胃溃疡大鼠表皮生长因子及其受体表达的影响

[目的]观察健中愈疡片对乙酸诱导胃溃疡大鼠血清表皮生长因子（EGF）水平和胃溃疡边缘表皮生长因子受体（EGFR）表达的影响。[方法]制备乙酸诱导大鼠胃溃疡模型，分别予健中愈疡片、雷尼替丁和0．85％氯化钠液治疗14d，用放射免疫分析法测定大鼠血清EGF水平，免疫组织化学染色法检测胃溃疡边缘EGFR表达。[结果]造模3d时，胃溃疡模型组大鼠的血清EGF水平明显高于正常对照组，胃溃疡边缘EGFR表达比正常对照组明显增加。治疗14d后，与雷尼替丁组和0．85％氯化钠液组比较，健中愈疡片组的血清EGF水平显著减少（P〈0．01），而胃溃疡边缘EGFR表达显著增加（P〈0．01）。[结论]血清EGF水平可以作为反映胃肠黏膜完整性的一个监控指标，健中愈疡片能够减少血清EGF水平和增加胃溃疡边缘EGFR表达，这可能是其加速乙酸诱导胃溃疡愈合的主要作用机制。     

糖皮质激素对老年鼻息肉患者表皮生长因子和表皮生长因子受体的表达影响及其临床作用

目的探讨糖皮质激素治疗老年鼻息肉患者的效果及其对息肉组织中表皮生长因子(EGF)和表皮生长因子受体(EGFR)表达水平的影响。方法纳入2014年1月至2016年8月在我院接受糖皮质激素治疗的60例老年鼻息肉患者(息肉组)及鼻中隔偏曲患者20例(对照组)。息肉组患者采用布地奈德喷剂治疗12周,分别于治疗前、治疗后采集息肉组织及对照组鼻黏膜组织进行免疫组化染色及逆转录-多聚酶链反应(RT-PCR)检查,对比两组EGF和EGFR蛋白及信使核糖核酸(mRNA)表达水平。计量资料以均数±标准差表示,两组间比较采用t检验。结果息肉组患者的鼻息肉病变评分情况:治疗前(2.48±0.77)分,治疗2周后(2.11±0.68)分,治疗6周后(1.57±0.49)分,治疗12周后(1.29±0.64)分;鼻息肉病变评分呈逐渐降低趋势,各时间点比较差异具有统计学意义(P0.05)。息肉组在治疗前、治疗后的EGF、EGFR蛋白表达水平和mRNA表达水平均高于对照组(P0.05);息肉组治疗12周后鼻息肉组织中EGF和EGFR蛋白表达水平和mRNA表达水平较治疗前均显著降低(P0.05)。结论糖皮质激素治疗老年鼻息肉患者的效果肯定,其作用机制与抑制鼻息肉组织中EGF及EGFR表达有关。     

Human cancers converge at the HIF-2α oncogenic axis

Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579–591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287–290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280–1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2α, an element of the oxygen-sensing machinery. Inhibition of HIF-2α prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non–small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2α exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2α oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2α as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.     

Prognostic value of EGFR and p-EGFR in nasopharyngeal carcinoma: A systematic review and meta-analysis

Purpose:To evaluate the prognostic effect and clinical significance of epidermal growth factor receptor and its phosphorlated form (EGFR/p-EGFR) in nasopharyngeal carcinoma.Methods:A systematic review and meta-analysis was designed. We visited PubMed, Embase, China National Knowledge Infrastructure Database, Database of Chinese sci-tech periodicals, WanFang Database, and China Biology Medicine disc to search for Chinese and English publications of prospective studies and retrospective studies investigating the association of EGFR/p-EGFR and nasopharyngeal carcinoma prognosis from inception to April 2021. The inclusion criteria were that the samples should be pathologically confirmed as nasopharyngeal carcinoma and the expression of EGFR/p-EGFR should be detected via immunohistochemistry; the study should analyze the prognostic significance of EGFR/p-EGFR in nasopharyngeal carcinoma; hazard ratio (HR) and 95% confidence interval (CI) should be reported in the study or could be derived from survival curves; and the outcomes of the study should include overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS).Results:A total of 18 studies evaluating 1451 samples were included. For studies that reported OS as an outcome, EGFR overexpression indicated worse OS of nasopharyngeal carcinoma patients. The heterogeneity between studies was high (I² = 91%, P < .01), and a random-effect model was used to combine the effect size (HR = 1.71, 95% CI [1.21, 2.41], P < .01). Further sensitivity analysis and prespecified subgroup analysis were performed to detect the source of heterogeneity, and the results showed that the heterogeneity could not be eliminated. Publication bias assessed by funnel plots and Begg test and Egger test was low (Begg test: P = .846 and Egger test: P = .074). p-EGFR was not correlated with the OS of nasopharyngeal carcinoma patients (HR = 1.01, 95% CI [0.88, 1.15], P = .92). For studies that reported DFS, EGFR overexpression was associated with worse DFS in patients with nasopharyngeal carcinoma (HR = 2.53, 95% CI [1.84, 3.47], P < .01). For studies that reported PFS, EGFR overexpression was not correlated with the PFS of nasopharyngeal carcinoma patients (HR = 1.86, 95% CI [0.90, 3.82], P = .09). For studies that reported DMFS, EGFR overexpression was not correlated with the DMFS of nasopharyngeal carcinoma patients, and high heterogeneity between studies was detected (I² = 97%, P < .01). A random-effect model was used to combine the effect size (HR = 1.80, 95% CI [0.56, 5.76], P = .32). A sensitivity analysis was conducted. Publication bias was detected to be low (Begg test: P = .817 and Egger test: P = .954). There was no correlation between p-EGFR overexpression and DMFS in patients with nasopharyngeal carcinoma (HR = 1.20, 95% CI [0.95, 1.52], P = .12).Conclusion:In nasopharyngeal carcinoma patients, EGFR overexpression could be used as a biomarker that predicts poor OS and DFS, but not a prognostic biomarker for PFS and DMFS. The overexpression of p-EGFR was not shown to be associated with the prognosis of nasopharyngeal carcinoma patients and could not be used as a prognostic biomarker.Ethics and dissemination:This study was registered on the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), and reported as stated by the Preferred Reporting Items for Systematic reviews and Meta-Analyses. Neither ethical approval nor informed consent was required since this study was conducted based on previous publications.INPLASY registration number:INPLASY 202150010     

Companion diagnostics for the targeted therapy of gastric cancer

Gastric cancer is the fourth most common type ofcancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer.     

非小细胞肺癌组织中EGFR、VEGFR-3、PDGFR的表达及临床病理学评价

目的探讨表皮生长因子受体（EGFR）、血管内皮生长因子受体-3（VEGFR-3）和血小板源性生长因子受体（PDGFR）的表达与非小细胞肺癌（NSCLC）生物学行为的关系及其内在联系。方法用免疫组化SP法对205例Ⅰ-Ⅲ期NSCLC根治手术后的标本进行EGFR、VEGFR-3、PDGFR表达检测。结果 EGFR、VEGFR-3、PDGFR的阳性表达率分别为36.1%、90.2%、61.5%。EGFR的表达与淋巴结转移个数有关;VEGFR-3表达与N分期、胸膜侵犯有关。PDGFR的表达评分与VEGFR-3的表达评分呈正相关,r=0.255,P=0.001。结论 EGFR、VEGFR-3是NSCLC淋巴转移与局部侵犯的相关因素,PDGFR与VEGFR-3可能存在某种内在联系,对多靶点靶向药物的研发及靶向治疗药物的联合应用具有提示意义。     

大肠癌组织中表皮生长因子受体的定量检测

本文用受体结合法检测了２８例大肠癌，癌周组织和１８例正常结肠组织中表皮生长因子受体（ＥＧＦ－Ｒ）的含量。结果示大肠癌组织中ＥＧＦ－Ｒ的量１１．８３±１０．３６ｆｍｏｌ／ｍｇ高于癌周组织４．８１±２．４４ｆｍｏｌ／ｍｇ。更高于正常肠组织１．８８±１．０２ｆｍｏｌ／ｍｇ。统计分析示有淋巴转移的晚期肿瘤ＥＧＦ－Ｒ较高，另中高分化癌中ＥＧＦ－Ｒ的含量也高于低分化癌。     

善胃系列方治疗胃癌前期病变的临床及基础研究

[目的]观察善胃系列方对胃癌前期病变的临床效果，探讨其逆转胃癌前期病变的分子机制。[方法]154例胃癌前期病变患者随机分为2组，治疗组106例，口服善胃系列方中药，根据辨证分型又分为3组：血瘀热毒型（善胃Ⅰ号方）组34例，阴虚有热型（善胃Ⅱ号方）组43例，气阴两虚型（善胃Ⅲ号方）组29例；对照组48例，口服猴头菌片。连续治疗6个月，观察2组患者临床症状改善、胃镜所见及胃黏膜病理组织学改善情况；采用免疫组化法检测治疗前后胃黏膜组织表皮生长因子（EGF）、表皮生长因子受体（EGFR）、转化生长因子α（TGF-α）的表达。[结果]治疗组总有效率为83．96％，显效率为45．28％；对照组分别为29．17％及6．25％，治疗组显著优于对照组（P〈0．01）。胃癌前病变患者胃黏膜的EGF、EGFR、TGF-α的表达水平较高，善胃系列方均可降低其表达水平。[结论]善胃系列方对胃癌前期病变的临床效果明显优于猴头菌片，其作用可能与抑制胃癌前期病变时胃黏膜EGF、EGIR、TGF-α的过度表达有关。     

Fast rebinding increases dwell time of Src homology 2 (SH2)-containing proteins near the plasma membrane

Receptor tyrosine kinases (RTKs) control a host of biological functions by phosphorylating tyrosine residues of intracellular proteins upon extracellular ligand binding. The phosphotyrosines (p-Tyr) then recruit a subset of ～100 Src homology 2 (SH2) domain-containing proteins to the cell membrane. The in vivo kinetics of this process are not well understood. Here we use total internal reflection (TIR) microscopy and single-molecule imaging to monitor interactions between SH2 modules and p-Tyr sites near the cell membrane. We found that the dwell time of SH2 modules within the TIR illumination field is significantly longer than predictions based on chemical dissociation rate constants, suggesting that SH2 modules quickly rebind to nearby p-Tyr sites after dissociation. We also found that, consistent with the rebinding model, the effective diffusion constant is negatively correlated with the respective dwell time for different SH2 domains and the dwell time is positively correlated with the local density of RTK phosphorylation. These results suggest a mechanism whereby signal output can be regulated through the spatial organization of multiple binding sites, which will prompt reevaluation of many aspects of RTK signaling, such as signaling specificity, mechanisms of spatial control, and noise suppression.     

Cimetidine inhibits epidermal growth factor-induced cell signaling

BACKGROUND: Cimetidine, a histamine-2 (H2) receptor antagonist, has been demonstrated to have anticancer effects on colorectal cancer, melanoma and renal cell carcinoma. In the current study, we clarified that cimetidine inhibits both epidermal growth factor (EGF)-induced cell proliferation and migration in hepatocellular carcinoma (HCC) cell lines. METHOD: HCC cell lines (Hep3B, HLF, SK-Hep-1, JHH-2, PLC/PRF/5 and HLE) were used and cell proliferation was assessed by [3H]-thymidine incorporation assay. Cell migration was measured by in vitro cell migration assay. Biological effects of cimetidine were assessed with human EGF receptor (EGFR)-expressing mouse fibroblast cells (NR6-WT). The autophosphorylation of EGFR and the activation of other downstream effectors were analyzed by immunoprecipitation and immunoblotting. The concentration of intracellular cyclic AMP (cAMP) was measured by competitive enzyme immunoassay. RESULTS: Cimetidine inhibited both EGF-induced cell proliferation and migration in Hep3B, HLF, SK-Hep-1 and JHH-2, while cimetidine did not affect EGF-induced cell proliferation and migration in PLC/PRF/5 and HLE. Cimetidine was revealed to disrupt the EGF-induced autophosphorylation of EGFR and its downstream effectors, mitogen activated protein kinases and phospholipase C-gamma. To define the molecular basis of this negative regulation, we identified that cimetidine significantly decreased intracellular cAMP levels and that decrement of cAMP inhibited autophosphorylation of EGFR. The cell permeable cAMP analog, CPT-cAMPS reversed the cimetidine-induced inhibition of EGF-induced cell proliferation and cell migration by restoring autophosphorylation of EGFR. CONCLUSION: Cimetidine inhibited EGF-induced cell proliferation and migration in HCC cell lines by decreasing the concentration of intracellular cAMP levels. Cimetidine may be a candidate chemopreventive agent for HCC.     

大肠癌EGFR、HER-2、VEGF表达特点及其对分子靶向治疗的指导意义

目的:探讨大肠癌中表皮生长因子受体(EGFR)、人类表皮生长因子受体-2(HER-2)和血管内皮生长因子(VEGF)的表达特点及其对大肠癌分子靶向治疗的指导意义.方法:随机选取2005-05/2009-03中国人民解放军空军总医院普通外科行根治性手术的大肠癌患者78例. 应用免疫组织化学法检测大肠癌肿瘤组织中EGFR、HER-2、VEGF的表达, 并结合其临床病理特点进行回顾性分析.结果:EGF R、HE R-2、VEGF在大肠癌中的阳性表达率依次为38 . 5%( 30 / 78 ) 、53.8%(42/78)、41.0%(32/78). 三者的表达与性别、年龄、肿瘤部位、分化类型无关, 而与肿瘤的大小、侵袭深度和转移密切相关.EGFR与HER-2及VEGF, HER-2与VEGF在大肠癌肿瘤组织中表达呈正相关(r = 0.421,0.484, 0.469, P = 0.019, 0.012, 0.016).结论:EGFR、HER-2、VEGF的表达参与大肠癌的生长、侵袭和转移过程. 三者的联合检测可作为判断大肠癌预后、筛选高危转移患者的有效指标, 同时, 也可用于指导大肠癌的靶向药物治疗.     

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

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/EGFR-dependent pathologies.ADAM17 (a disintegrin and metalloprotease 17) is a membrane-anchored metalloproteinase that controls two major signaling pathways with important roles in development and disease, the EGF receptor (EGFR) pathway and the proinflammatory tumor necrosis factor α (TNF-α) pathway (1–5). 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, 6–14). 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). A hallmark feature of ADAM17 is its rapid response to various activators of cellular signaling pathways (21–23), which is presumably important to allow a rapid response to injury and to maintain the skin and intestinal barrier. The rapid activation of ADAM17 is controlled by its transmembrane domain whereas the cytoplasmic domain is dispensable in this context (22), suggesting that ADAM17 is regulated by one or more other membrane proteins, yet the underlying mechanism has remained enigmatic.Recent studies have shown that the maturation and function of ADAM17 in myeloid cells depend on inactive Rhomboid 2 (iRhom2), a catalytically inactive member of the Rhomboid family of seven membrane-spanning intramembrane serine proteinases (24–28). Myeloid cells lacking iRhom2 release very little TNF-α in response to activation of Toll-like receptor 4 by lipopolysaccharide (LPS) (24, 26, 28). Therefore, mice lacking iRhom2 are protected from the detrimental effects of TNF-α in mouse models for septic shock and inflammatory arthritis, similar to conditional knockout mice lacking ADAM17 in myeloid cells (11, 26, 29). However, iRhom2^−/− (iR2^−/−) mice are viable with no evident spontaneous pathological phenotypes (26, 29), whereas Adam17^−/− (A17^−/−) mice die shortly after birth (3). A major unresolved question has therefore been whether iRhom2 and the related iRhom1 are the long-sought-after regulators of the function of ADAM17-dependent EGFR signaling in vivo. Here we generate iRhom1^−/− (iR1^−/−) mice, which are viable and healthy, and report that iR1/2^−/− double knockout mice closely resemble mice lacking ADAM17 or the EGFR, providing the first genetic evidence, to our knowledge, that the principal function of iRhoms1/2 during mouse development is to control ADAM17/EGFR signaling.