Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family

Toyoda, Hitoshi; Komurasaki, Toshi; Uchida, Daisuke; Morimoto, Shigeo

doi:10.1042/bj3260069

Cited by 120 publications

(92 citation statements)

References 60 publications

(63 reference statements)

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“…High expression levels of the epiregulin gene have been shown in a number of cancer cell lines and activation of the Ki-Ras signaling pathway in colon cancer cells has been linked to the deregulation of epiregulin expression (Baba et al, 2000). Among the epidermal growth factor receptor ligands, epiregulin is distinguished by its more potent mitotic activity, the ability to bind various heterodimeric ErbB receptors (Shelly et al, 1998), and its unusual expression pattern, mainly in peripheral blood monocytes, macrophages and the placenta in normal human tissues, as well as in various types of epithelial tumor cell lines (Toyoda et al, 1997). In the mouse, epiregulin is expressed by tissue resident and peritoneal macrophages in vivo and its expression in macrophages is induced in response to the toll-like receptor agonists LPS and peptidoglycan in vitro (Shirasawa et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…One of the candidate growth factors known to be critical in SCC development is epiregulin, a potent member of the epidermal growth factor family (Toyoda et al, 1997). We examined the epiregulin gene expression in the lungs of C57BL/6J mice during the course of infection with MTB using quantitative RT-PCR of total lung tissue.…”

Section: Chronic Mtb Infection Causes Squamous Cell Carcinomamentioning

confidence: 99%

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Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

et al. 2009

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Coexistence of pulmonary tuberculosis (TB) and lung cancer in clinic poses significant challenges for the diagnostic and treatment of both diseases. Although association of chronic inflammation and cancer is welldocumented, causal relationship between TB infection and lung cancer are not understood. We present experimental evidence that chronic TB infection induces cell dysplasia and squamous cell carcinoma (SCC) in a lung-specific manner. First, squamous cell aggregates consistently appeared within the lung tissue associated with chronic TB lesions, and in some cases resembled SCCs. A transplantable tumor was established after the transfer of cells isolated from TB lung lesions into syngeneic recipients. Second, the (Mycobacterium tuberculosis) MTB-infected macrophages play a pivotal role in TBinduced carcinogenesis by inducing DNA damage in their vicinity and by the production of a potent epidermal growth factor epiregulin, which may serve as a paracrine survival and growth factor responsible for squamous metaplasia and tumorigenesis. Third, lung carcinogenesis during the course of chronic TB infection was more pronounced in animals with severe lung tissue damage mediated by TB-susceptibility locus sst1. Together, our experimental findings showed a causal link between pulmonary TB and lung tumorigenesis and established a genetic model for further analysis of carcinogenic mechanisms activated by TB infection.

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Section: Discussionmentioning

confidence: 99%

Section: Chronic Mtb Infection Causes Squamous Cell Carcinomamentioning

confidence: 99%

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

et al. 2009

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“…In the intact animal, the expression of epiregulin transcript is detected during the early stages of embryonic life (Toyoda et al, 1995b). Furthermore, results from our laboratory have shown that the human epiregulin peptide deduced from cDNA sequence is highly homologous to mouse epiregulin and is biologically active (Toyoda et al, 1997). Although epiregulin inhibits the binding of [ 125 I]EGF to EGFR on A431 cells more weakly than EGF (Toyoda et al, 1995a), the direct binding of epiregulin to ErbB receptors has not been analysed.…”

Section: Introductionmentioning

confidence: 99%

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

et al. 1997

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Epiregulin is a member of the epidermal growth factor (EGF) family, and has certain characteristics that are di erent from that of EGF, including mitogenic responses and binding to EGF receptor (EGFR). Epiregulin may also have another cell surface receptor and/or induces di erent receptor heterodimerizations for intracellular signaling. We investigated the binding ability of epiregulin to four ErbB family receptors using four human breast carcinoma cell lines that expressed di erent subsets of receptors. Chemical cross-linking experiments showed that [ 125 I]epiregulin directly bound to each of EGFR and ErbB-4 but not to ErbB-2 and ErbB-3. Furthermore, although epiregulin stimulated tyrosine phosphorylation of all four ErbB receptors, the main intracellular signal was mediated by ErbB-4 and/or EGFR. The pattern of activation of ErbB family receptors was di erent from that of other EGF-related ligands. Our ®ndings indicate that ErbB-4 and EGFR are receptors for epiregulin, and suggest that EGFrelated ligands transduce signals for di erent biological responses by the hierarchical mechanism.

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“…EREG is proteolytically cleaved by a disintegrin and a metalloprotease 17 (ADAM17) to release soluble ligand that binds to and activates ERBB1/EGFR and ERBB4/Her4 (2,10,11). Expression of EREG in adults is restricted (12)(13)(14), but EREG is overexpressed in a number of human breast and colorectal cancer cell lines and tumors (15)(16)(17)(18)(19). EREG also has been implicated as a "metastasis driver" in breast cancer cells selected to metastasize to the lung (20).…”

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confidence: 99%

Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

Singh

Bogatcheva²,

Washington

et al. 2013

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

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Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXΦ: Y 156 ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin-Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells.epithelial transformation | growth factor trafficking | receptor tyrosine kinase | protein sorting U nder normal physiological conditions, binding of endogenous ligand to EGF receptor (EGFR) is required for initiation of signal transduction. In polarized epithelial cells, EGFR is thought to be restricted to the basolateral surfaces (1). All seven EGFR ligands are produced as type 1 transmembrane proteins (2). Newly synthesized ligands are inserted into the plasma membrane, whereupon they undergo ectodomain cleavage to release soluble growth factor. We previously studied the biosynthesis and trafficking of EGF, TGF-α (TGFA), and amphiregulin (AREG) in polarized Madin-Darby canine kidney (MDCK) cells (3-5). These ligands have distinct motifs that govern their basolateral sorting (6-8). Of clinical relevance is a germline mutation in the basolateral sorting motif of EGF in individuals with isolated renal hypomagnesemia (9). In this autosomal recessive disorder, loss of EGF delivery to the basolateral surface impairs EGFR activity in the distal convoluted tubules, which is required for efficient magnesium absorption.Here we undertook the study of another EGFR ligand, epiregulin (EREG). EREG is proteolytically cleaved by a disintegrin and a metalloprotease 17 (ADAM17) to release soluble ligand that binds to and activates ERBB1/EGFR and ERBB4/Her4 (2, 10, 11). Expression of EREG in adults is restricted (12-14), but EREG is overexpressed in a number of human breast and colorectal cancer cell lines and tumors (15)(16)(17)(18)(19). EREG also has been implicated as a "metastasis dri...

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Distribution of mRNA for human epiregulin, a differentially expressed member of the epidermal growth factor family

Cited by 120 publications

References 60 publications

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

Transformation of polarized epithelial cells by apical mistrafficking of epiregulin

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