Altered expression of epimorphin in ulcerative colitis

Shirasaka, Tomoyuki; Iizuka, Masahiro; Yukawa, Michihiro; Hirai, Yohei; Horie, Yasuo; Itou, Hiroaki; Konno, Shiho; Fukushima, Tsuneo; Watanabe, Sumio

doi:10.1046/j.1440-1746.2003.02972.x

Cited by 12 publications

(15 citation statements)

References 31 publications

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“…The identification of the epimorphin binding cleft may facilitate development of inhibitors capable of blocking the binding of epimorphin to its cell surface receptors. Moreover, because epimorphin has been implicated in normal and pathological development of a number of organs in addition to the breast, including intestine (10,61), lung (62,63), pancreas (7), liver (64,65), cartilage (66), and hair (9, 67), our identification of a key epimorphin interaction domain may be applicable to investigations of these organs in both normal development and in neoplasia.…”

Section: Discussionmentioning

confidence: 99%

Homology with Vesicle Fusion Mediator Syntaxin-1a Predicts Determinants of Epimorphin/Syntaxin-2 Function in Mammary Epithelial Morphogenesis

Chen

Nelson

Khauv

et al. 2009

Journal of Biological Chemistry

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We have shown that branching morphogenesis of mammary ductal structures requires the action of the morphogen epimorphin/syntaxin-2. Epimorphin, originally identified as an extracellular molecule, is identical to syntaxin-2, an intracellular molecule that is a member of the extensively investigated syntaxin family of proteins that mediate vesicle trafficking. We show here that, although epimorphin/syntaxin-2 is highly homologous to syntaxin-1a, only epimorphin/syntaxin-2 can stimulate mammary branching morphogenesis. We construct a homology model of epimorphin/syntaxin-2 based on the published structure of syntaxin-1a, and we use this model to identify the structural motif responsible for the morphogenic activity. We identify four residues located within the cleft between helices B and C that differ between syntaxin-1a and epimorphin/syntaxin-2; through site-directed mutagenesis of these four amino acids, we confer the properties of epimorphin for cell adhesion, gene activation, and branching morphogenesis onto the inactive syntaxin-1a template. These results provide a dramatic demonstration of the use of structural information about one molecule to define a functional motif of a second molecule that is related at the sequence level but highly divergent functionally.Branching morphogenesis is a developmental process involved in the formation of many organs, including mammary gland, lung, kidney, and salivary gland. In the mammary gland, branching morphogenesis allows the primitive anlage to develop into the highly ramified mammary ductal tree. Investigations of the signaling processes involved in mammary ductal branching have revealed that branching requires the presence of a growth factor and the morphogen epimorphin (1). Epimorphin binds to mammary epithelial cells through ␣v-integrins (2), activating morphogenic processes that are dependent upon the transcription factor CCAAT/enhancer-binding protein-␤ (C/EBP␤) 5 (3), and mediating branching and invasion into the extracellular matrix through activation of matrix metalloproteinase-3 (MMP3) (4). Although epimorphin is required for branching morphogenic processes, overexpression of epimorphin can lead to pathological consequences, including ductal hyperplasia and mammary cancer (3, 5). Epimorphin plays a role in morphogenesis of other epithelial organs as well, including kidney (6), pancreas (7,8), hair (9), intestine (10, 11), and lung (12).Although epimorphin was first identified as an extracellular morphogen through the use of function-blocking antibodies in lung and skin organ culture assays (12, 13), the same molecule was later found to function in the cytoplasm as syntaxin-2, a member of the syntaxin family of proteins that controls vesicle fusion (14, 15). However, the idea that epimorphin/syntaxin-2 might have distinct roles dependent upon its location on the outside or inside of the plasma membrane is controversial (14 -16), in part because epimorphin lacks a canonical peptide signal sequence to direct extracellular localization through the ER/Golgi path...

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Section: Discussionmentioning

confidence: 99%

Homology with Vesicle Fusion Mediator Syntaxin-1a Predicts Determinants of Epimorphin/Syntaxin-2 Function in Mammary Epithelial Morphogenesis

Chen

Nelson

Khauv

et al. 2009

Journal of Biological Chemistry

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“…There have been several findings suggesting this relationship may also function in humans. EPM has been reported to be up-regulated in human patients with activated ulcerative colitis, an autoimmune disease causing chronic inflammation of the colon that often results in cancer later in life (15). Furthermore, another member of the syntaxin family that is 70% homologous to EPM, syntaxin 1A, is thought to be deregulated in human small-cell lung carcinoma and has been associated with a more aggressive course of undifferentiated carcinoma of the colon and rectum (16,17).…”

Section: Discussionmentioning

confidence: 99%

Epimorphin Overexpression in the Mouse Mammary Gland Promotes Alveolar Hyperplasia and Mammary Adenocarcinoma

Bascom

Fata²,

Hirai³

et al. 2005

Cancer Research

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Epimorphin/syntaxin-2 (EPM) is a plasma membraneanchored protein that has at least two distinct functions depending on its membrane topology: vesicle fusion when localized to the cytoplasmic surface and morphogenic signaling when localized to the extracellular surface. Transgenic mice that express full-length extracellular EPM fused to the NH 2 -terminal signal sequence of interleukin-2, under the control of the whey acidic protein (WAP) gene promoter, exhibit aberrant mammary gland morphogenesis associated with increased expression of CCAAT enhancer binding protein B (C/EBPB). Here we report that aged nulliparous and uniparous female WAP-EPM transgenic mice develop alveolar hyperplasias and well-differentiated adenocarcinomas that express high levels of C/EBPB, keratin-14, matrix metalloproteinase-3, and B-catenin. This study reveals another pathway in which overexpression and alteration of a normal morphogenic process promote the development of cancer in the mammary gland. (Cancer Res 2005; 65(19): 8617-21)

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“…[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Angiogenesis plays an important role in a wide range of physiological processes including embryogenesis, wound healing, growth of solid tumor, and rheumatoid arthritis. [3][4][5]21,29,30 It is thought that angiogenesis is regulated by a balance of angiogenic factors and angiogenesis inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…2 In this context, angiogenesis plays an important role as a protective factor in regeneration of injured tissues, [3][4][5] and investigations focused on several angiogenic factors in IBD have been increasing. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Numerous angiogenic factors have been identified to date. Among them, vascular endothelial growth factor (VEGF) is thought to play a principal role by stimulating migration and proliferation of endothelial cells (ECs) and the expression of angiogenesis-related genes.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Thus, the VEGF-Ets-1 cascades play important roles in angiogenesis of several tissues, and abnormalities of these cascades might result in incomplete wound repair or persistence of tissue injury. Although previous studies investigated the expression of VEGF, 6-10 basic fibroblast growth factor (bFGF), 7,11,12 which is upstream of Ets-1, and MMPs, [14][15][16][17]19 downstream of Ets-1 in IBD, there have been no reports systemically investigating the VEGF-Ets-1 cascades in IBD. In this study, we precisely investigated each angiogenic factor in the VEGFEts-1 cascades in the colonic mucosa of IBD patients and first showed the alteration of these angiogenic factors between UC and CD.…”

Section: Introductionmentioning

confidence: 99%

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Altered expression of angiogenic factors in the VEGF-Ets-1 cascades in inflammatory bowel disease

et al. 2004

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Altered expression of epimorphin in ulcerative colitis

Abstract: Our results suggest that altered expression of epimorphin contributes to impaired healing and chronic inflammation in the colonic mucosa of UC patients.

Cited by 12 publications

References 31 publications

Homology with Vesicle Fusion Mediator Syntaxin-1a Predicts Determinants of Epimorphin/Syntaxin-2 Function in Mammary Epithelial Morphogenesis

Homology with Vesicle Fusion Mediator Syntaxin-1a Predicts Determinants of Epimorphin/Syntaxin-2 Function in Mammary Epithelial Morphogenesis

Epimorphin Overexpression in the Mouse Mammary Gland Promotes Alveolar Hyperplasia and Mammary Adenocarcinoma

Altered expression of angiogenic factors in the VEGF-Ets-1 cascades in inflammatory bowel disease

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