Distribution and isoforms of epimorphin in carbon tetrachloride‐induced acute liver injury in mice

Segawa, Daisuke; Miura, Kouichi; Goto, Takashi; Ohshima, Shigetoshi; Mikami, Koji; Yoneyama, Kazuo; Shibuya, Tomomi; Watanabe, Dai; Kataoka, Ei; Yoshino, Ryutaro; Watanabe, Sumio

doi:10.1111/j.1440-1746.2005.03944.x

Cited by 12 publications

(17 citation statements)

References 22 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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“…Nevertheless, our finding that epimorphin inhibition caused persistently increased macrophage and myofibroblast infiltration, cell proliferation and loss of E-cadherin expression on tubular epithelial cells strongly suggests that epimorphin functions basically in the repair of renal fibrosis possibly through mesenchymal-epithelial interaction. Considering what we know of tissue damage in other organs, [11][12][13][14][15] we assume that when a kidney is injured epimorphin functions as a repair protein and has a role similar to its role as a morphogen when a kidney develops.…”

Section: Discussionmentioning

confidence: 99%

“…[4][5][6][7][8][9][10] In addition, several investigators have reported changes in the distribution of epimorphin-positive cells in inflammatory diseases of the lung and liver. [11][12][13][14] Epimorphin not only regulates morphogenesis but also functions as a mesenchymal regulator of epithelial repair. 10,12,14,15 The importance of epithelial-mesenchymal transition in the development of renal fibrosis has been extensively analyzed and characterized.…”

mentioning

confidence: 99%

“…[11][12][13][14] Epimorphin not only regulates morphogenesis but also functions as a mesenchymal regulator of epithelial repair. 10,12,14,15 The importance of epithelial-mesenchymal transition in the development of renal fibrosis has been extensively analyzed and characterized. 2,[16][17][18][19][20][21][22] However, there have been no reports of studies analyzing the involvement of epimorphin, which is the key molecule for epithelial-mesenchymal interaction, in renal fibrosis.…”

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confidence: 99%

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Involvement of epimorphin in the repair of experimental renal fibrosis in mice

Yamada¹,

Oda²,

Higashi³

et al. 2010

Laboratory Investigation

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Interaction between epithelial cells and mesenchymal cells is essential in normal organ morphogenesis and in tissue repair after injury. Epimorphin, a mesenchymal protein that regulates epithelial morphogenesis through epithelialmesenchymal interactions, has recently attracted attention as an important modulator of tissue repair. In this study we analyzed the role of epimorphin in renal fibrosis. We first found a progressive increase in epimorphin expression corresponding to the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). To determine whether this expression has a role in the repair or progression of renal fibrosis, we analyzed a model of renal fibrosis repair, the UUO-release (UUO-R) model. Epimorphin expression was increased at 3 and 7 days after the UUO-R rather than on the day of release, but was decreased at 21 days after the release. Inhibition of endogenous epimorphin with antiepimorphin antibody (MC-1) significantly delayed the repair of fibrosis. When compared with normal-IgG-injected mice, MC-1-injected mice showed significantly decreased renal matrix metalloproteinase (MMP)-2 and MMP-9 expressions by western blotting and increased expression of TGF-b and collagen-I mRNA by real-time RT-PCR. Recombinant epimorphin induced prominent increases in MMP-2 and MMP-9 activities in the culture media of renal interstitial fibroblasts in vitro. These findings indicate that epimorphin has a pivotal role in the repair of renal fibrosis by modulating both extracellular matrix (ECM) degradation and its production.

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“…Epimorphin is one of the ligands of the integrin aVb1 receptor located on the cellular membrane [31] and is expressed in hepatic stellate cells and myofibroblasts during liver injury in mice [32,33]. After binding to its receptor, epimorphin signals regulate normal bile duct formation by mediating mitosis orientation [34].…”

Section: Discussionmentioning

confidence: 99%

A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

et al. 2010

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Distribution and isoforms of epimorphin in carbon tetrachloride‐induced acute liver injury in mice

Abstract: Epimorphin is involved in tissue repair following a single injection of carbon tetrachloride, in which distribution and the quantity of epimorphin expression are important, particularly in maintaining hepatocyte function.

Cited by 12 publications

References 22 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

Involvement of epimorphin in the repair of experimental renal fibrosis in mice

A polymorphism in the integrin αV subunit gene affects the progression of primary biliary cirrhosis in Japanese patients

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