Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription

Isokane, Mayumi; Hieda, Miki; Hirakawa, Satoshi; Shudou, Masachika; Nakashiro, Koh‐ichi; Hashimoto, Koji; Hamakawa, Hiroyuki; Higashiyama, Shigeki

doi:10.1242/jcs.031443

Cited by 39 publications

(58 citation statements)

References 39 publications

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“…8C). We speculate that the residual immunoreactivity in the nuclear fraction might be associated with full-length BTC-DE that had been detected biochemically in the nuclear fraction; this is also consistent with recent reports for nuclear trafficking of other ErbB ligands Higashiyama et al, 2008;Isokane et al, 2008). Thus, the palmitoylated BTC-ICD, unlike the non-palmitoylated version, is primarily localized to the nuclear membrane rather than trafficking into the nucleus.…”

Section: Palmitoylated Btc-icd Is Localized At the Nuclear Membranesupporting

confidence: 90%

“…The second pathway is receptor independent, termed reverse signaling, and involves nuclear localization and signaling by the ICD of the ligand precursor . Although the mechanisms for production and nuclear trafficking of each ICD seem to be distinct, a common feature of reverse signaling is the transcriptional regulation of gene expression (Bao et al, 2004;Bao et al, 2003;Hieda et al, 2008;Higashiyama et al, 2008;Isokane et al, 2008;Nanba et al, 2003). In the present study, we show that the BTC precursor (proBTC) can undergo sequential processing by ADAM10 and presenilin1/2-dependent -secretase to generate BTC-ICD.…”

Section: Discussionmentioning

confidence: 57%

“…Several ErbB-ligand precursors can translocate to the nucleus by distinct mechanisms and influence gene expression (Bao et al, 2003;Hieda et al, 2008;Higashiyama et al, 2008;Isokane et al, 2008). To determine whether the BTC-ICD translocates to the nucleus, constructs encoding the ICD of BTC with N-or Cterminal EGFP tags were generated (BTC-ICD-Only).…”

Section: Non-palmitoylated Btc-icd Translocates To the Nucleusmentioning

confidence: 99%

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Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Stoeck

Dempsey

2010

Journal of Cell Science

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SummaryBetacellulin (BTC) belongs to the family of epidermal growth factor (EGF)-like growth factors that are expressed as transmembrane precursors and undergo proteolytic ectodomain shedding to release soluble mature ligands. BTC is a dual-specificity ligand for ErbB1 and ErbB4 receptors, and can activate unique signal-transduction pathways that are beneficial for the function, survival and regeneration of pancreatic b-cells. We have previously shown that BTC precursor (proBTC) is cleaved by ADAM10 to generate soluble ligand and a stable, transmembrane remnant (BTC-CTF). In this study, we analyzed the fate of the BTC-CTF in greater detail. We demonstrated that proBTC is cleaved by ADAM10 to produce BTC-CTF, which then undergoes intramembrane processing by presenilin-1-and/or presenilin-2-dependent -secretase to generate an intracellular-domain fragment (BTC-ICD). We found that the proBTC cytoplasmic domain is palmitoylated and that palmitoylation is not required for ADAM10-dependent cleavage but is necessary for the stability and -secretase-dependent processing of BTC-CTF to generate BTC-ICD. Additionally, palmitoylation is required for nuclear-membrane localization of BTC-ICD, as demonstrated by the redistribution of non-palmitoylated BTC-ICD mutant to the nucleoplasm. Importantly, a novel receptor-independent role for BTC-ICD signaling is suggested by the ability of BTC-ICD to inhibit cell growth in vitro.

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Section: Palmitoylated Btc-icd Is Localized At the Nuclear Membranesupporting

confidence: 90%

Section: Discussionmentioning

confidence: 57%

Section: Non-palmitoylated Btc-icd Translocates To the Nucleusmentioning

confidence: 99%

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Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Stoeck

Dempsey

2010

Journal of Cell Science

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“…In contrast, other reports suggested that AREG has a tumor inhibitory function (2,17). Intriguingly, AREG translocates to the inner nuclear membrane to induce heterochromatinization, thereby suppressing transcription (7). In ovarian cells, AREG localizes in the nucleus (5, 6); however, nuclear function of AREG has remained to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…It is well established that AREG translocates to the plasma membrane; however, few reports showed that AREG localizes in the nucleus (5,6). Recent study has demonstrated that AREG translocates to the inner nuclear membrane by a retrograde trafficking and attenuates global transcription (7). Taken together, AREG has multiple functions not only as a ligand for EGFR.…”

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confidence: 99%

Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage

Taira

Yamaguchi

Kimura

et al. 2013

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

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Upon DNA damage, tumor suppressor p53 determines cell fate by repairing DNA lesions to survive or by inducing apoptosis to eliminate damaged cells. The decision is based on its posttranslational modifications. Especially, p53 phosphorylation at Ser46 exerts apoptotic cell death. However, little is known about the precise mechanism of p53 phosphorylation on the induction of apoptosis. Here, we show that amphiregulin (AREG) is identified for a direct target of Ser46 phosphorylation via the comprehensive expression analyses. Ser46-phosphorylated p53 selectively binds to the promoter region of AREG gene, indicating that the p53 modification changes target genes by altering its binding affinity to the promoter. Although AREG belongs to a family of the epidermal growth factor, it also emerges in the nucleus under DNA damage. To clarify nuclear function of AREG, we analyze AREG-binding proteins by mass spectrometry. AREG interacts with DEAD-box RNA helicase p68 (DDX5). Intriguingly, AREG regulates precursor microRNA processing (i.e., miR-15a) with DDX5 to reduce the expression of antiapoptotic protein Bcl-2. These findings collectively support a mechanism in which the induction of AREG by Ser46-phosphorylated p53 is required for the microRNA biogenesis in the apoptotic response to DNA damage. microarray | Drosha | miRNA processing

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A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT‐0701 MAPS phase 3 trial

Maille

Levallet

Dubois

et al. 2022

Intl Journal of Cancer

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The Hippo pathway effector YAP is dysregulated in malignant pleural mesothelioma (MPM). YAP's target genes include the secreted growth factor amphiregulin (AREG), which is overexpressed in a wide range of epithelial cancers and plays an elusive role in MPM. We assayed the expression of YAP and AREG in MPM pathology samples and that of AREG additionally in plasma samples of patients from the randomized phase 3 IFCT-0701 Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) using immunohistochemistry and ELISA assays, respectively. MPM patients frequently presented high levels of tumor AREG (64.3%), a high cytosolic AREG expression being predictive of a better prognosis with longer median overall and progression-free survival. Surprisingly, tumor AREG cytosolic expression was not correlated with secreted plasma AREG. By investigating the AREG metabolism and function in MPM cell lines H2452, H2052, MSTO-211H and H28, in comparison with the T47D ER+ breast cancer cell line used as a positive control, we confirm that AREG is important for cell invasion, growth without anchorage, proliferation and apoptosis in mesothelioma cells. Yet, most of these MPM cell lines failed to correctly execute AREG posttranslational processing by metalloprotease ADAM17/tumor necrosis factor-alpha-converting enzyme (TACE) and extracell secretion. The favorable prognostic value of high cytosolic AREG expression in MPM patients could therefore be sustained by default AREG posttranslational processing and release. Thus, the determination of mesothelioma cell AREG content could be further investigated as a prognostic marker for MPM patients and used as a stratification factor in future clinical trials.amphiregulin, malignant pleural mesothelioma, YAP What's new?Malignant pleural mesothelioma (MPM) is an aggressive cancer, for which novel markers and therapeutic strategies are needed. Here, in MPM tumor specimens and controls, the authors investigated the prognostic potential of amphiregulin (AREG), a target of the transcriptional coactivator YAP, which drives MPM progression. Relative to controls, MPM patients with high cytosolic AREG expression had better prognosis, with longer survival.Analyses suggest that high cytosolic AREG expression results from sustained default AREG post-translational processing and release. AREG tumor expression may be a valuable tool for the identification of MPM patients with favorable prognosis, enabling adaptations in their therapeutic care.

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Plasma-membrane-anchored growth factor pro-amphiregulin binds A-type lamin and regulates global transcription

Cited by 39 publications

References 39 publications

Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Sequential and γ-secretase-dependent processing of the betacellulin precursor generates a palmitoylated intracellular-domain fragment that inhibits cell growth

Induction of amphiregulin by p53 promotes apoptosis via control of microRNA biogenesis in response to DNA damage

A defect of amphiregulin release predicted longer survival independently of YAP expression in patients with pleural mesothelioma in the IFCT‐0701 MAPS phase 3 trial

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