Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer

Qu, Le; Sha, Sha; Zou, Qian-Lei; Gao, Xinghua; Xiao, Ting; Chen, Hongdou; He, Chundi Chun

doi:10.2340/00015555-3189

Cited by 5 publications

(10 citation statements)

References 12 publications

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“…Our findings that cub and TOC mutations decreases levels of mature ADAM17 is in line with recent in vivo and ex vivo results (Siggs et al, 2014, Rabinowitsch et al, 2023. However, these findings are counterintuitive to the earlier reported elevated ADAM17 shedding activity (Brooke et al, 2014, Hosur et al, 2017, Hosur et al, 2018a, Hosur et al, 2018b.…”

Section: The Irhom2 N-terminus Differentially Regulates Adam17-mediat...supporting

confidence: 91%

“…Regions above 50% probability (ANCHOR2) and with a certain length are putative binding sites such as the highly conserved region which harbours all known TOC mutations. Our designed TOC site deletion ndTOC comprises the three main TOC mutations, but not the newest identified R197S (Qu et al, 2019). (F) We used the algorithm CONYAR (Kahveci-Türköz et al, 2023) to retrieve all available amino acid sequences of iRhom1 and iRhom2 from UniProtKB and compare them to identify highly conserved regions within the amino acid sequences of that gene.…”

Section: Resultsmentioning

confidence: 99%

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Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

Bläsius,

Ludwig,

Knapp

et al. 2023

Preprint

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The protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a regulatory site, encompassing all known TOC mutations, whose disruption increases constitutive ADAM17 activity. The larger cub deletion also includes the TOC site and thus also promotes increased constitutive ADAM17 activity. Furthermore, the cub mutation, but not the TOC mutation, causes severe reductions in stimulated shedding, binding and stability of ADAM17, suggesting the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17.

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Section: The Irhom2 N-terminus Differentially Regulates Adam17-mediat...supporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

Bläsius,

Ludwig,

Knapp

et al. 2023

Preprint

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show abstract

“…iRhom2 and ADAM17 levels increase during cancer progression and correlate with lower survival rates ( Agwae et al, 2020 ; Borrell-Pagès et al, 2003 ; Mochizuki and Okada, 2007 ; Walkiewicz et al, 2016 ; Xu et al, 2020 ; Zhou et al, 2006 , 2014 ). The most direct link between the iRhom proteins and cancer are mutations in the cytoplasmic domain of iRhom2, which cause a rare familial syndrome, tylosis with oesophageal cancer (TOC), characterised by a very high lifetime risk of developing oesophageal cancer ( Blaydon et al, 2012 ; Ellis et al, 2015 ; Mokoena et al, 2018 ; Qu et al, 2019 ; Saarinen et al, 2012 ). Increased activity of ADAM17 has been observed for iRhom2 TOC mutations ( Brooke et al, 2014 ; Maney et al, 2015 ) but, despite this strong genetic link, the precise mechanistic role of iRhoms in oncogenic signalling has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

“…Mokoena et al, 2018;Qu et al, 2019;Saarinen et al, 2012). Increased activity of ADAM17 Journal of Cell Science • Accepted manuscript…”

mentioning

confidence: 99%

iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells

Sieber

Stribbling

et al. 2022

Journal of Cell Science

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Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhoms, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells.

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“…iRhom2 and ADAM17 levels increase during cancer progression and correlate with lower survival rates (5-7, [15][16][17][18]. The most direct link between the iRhoms and cancer are mutations in the cytoplasmic domain of iRhom2, which cause a rare familial syndrome, tylosis with oesophageal cancer (TOC), characterised by a very high lifetime risk of developing oesophageal cancer (8, [19][20][21][22]. Increased activity of ADAM17 has been observed for iRhom2 TOC mutations (23,24) but, despite this strong genetic link, the precise mechanistic role of iRhoms in oncogenic signalling has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

iRhom2 regulates ERBB signalling to promote KRAS-driven oncogenesis

Sieber

Stribbling

et al. 2021

Preprint

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Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer (1, 2). Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhoms, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17 (3, 4). Here we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing iRhom2 as a central component of a positive feedback loop in lung cancer cells. Overall, the cytoplasmic domain of iRhom2 is a critical component of KRAS-induced oncogenesis of lung cancer cells. Both ADAM17 and iRhom2 have also been implicated in a wide range of other cancers (5–10), so the mechanism we have revealed may also have wider oncogenic significance.

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Whole Exome Sequencing Identified a Novel Mutation of the RHBDF2 Gene in a Chinese Family of Tylosis with Esophageal Cancer

Cited by 5 publications

References 12 publications

Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells

iRhom2 regulates ERBB signalling to promote KRAS-driven oncogenesis

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