Regulation of hyaluronan secretion into rabbit synovial joints <i>in vivo</i> by protein kinase C

Anggiansah, C. L.; Scott, David A.; Poli, A.; Coleman, Peter J.; Badrick, Ellena; Mason, Roger M.; Levick, J. R.

doi:10.1113/jphysiol.2003.038943

Cited by 21 publications

(39 citation statements)

References 47 publications

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“…Previous studies have shown that TNF-␣ activates PKC (62) and that PKC activation promotes HA synthesis by HAS (63). We now show that TNF-␣ stimulation promotes association of HA with CD44 at the cell periphery and that this association is accompanied by the interaction of CD44 with pERM, in particular with phosphorylated moesin.…”

Section: Tnf-␣ Promotes the Formation Of Ha⅐cd44⅐permmentioning

confidence: 49%

Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction

Takahashi

Nagano

Ishimoto

et al. 2010

Journal of Biological Chemistry

146

150

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Aberrant epithelial-mesenchymal transition (EMT) is involved in development of fibrotic disorders and cancer invasion.Alterations of cell-extracellular matrix interaction also contribute to those pathological conditions. However, the functional interplay between EMT and cell-extracellular matrix interactions remains poorly understood. We now show that the inflammatory mediator tumor necrosis factor-␣ (TNF-␣) induces the formation of fibrotic foci by cultured retinal pigment epithelial cells through activation of transforming growth factor-␤ (TGF-␤) signaling in a manner dependent on hyaluronan-CD44-moesin interaction. TNF-␣ promoted CD44 expression and moesin phosphorylation by protein kinase C, leading to the pericellular interaction of hyaluronan and CD44. Formation of the hyaluronan-CD44-moesin complex resulted in both cell-cell dissociation and increased cellular motility through actin remodeling. Furthermore, this complex was found to be associated with TGF-␤ receptor II and clathrin at actin microdomains, leading to activation of TGF-␤ signaling. We established an in vivo model of TNF-␣-induced fibrosis in the mouse eye, and such ocular fibrosis was attenuated in CD44-null mice. The production of hyaluronan and its interaction with CD44, thus, play an essential role in TNF-␣-induced EMT and are potential therapeutic targets in fibrotic disorders. The epithelial-mesenchymal transition (EMT)2 of epithelial cells is characterized by the loss of epithelial characteristics and the gain of mesenchymal attributes. During this transition, epithelial cells down-regulate cell-cell adhesion systems, lose their polarity, and acquire a mesenchymal phenotype associated with increased interaction with the extracellular matrix (ECM) and enhanced migratory capacity. The EMT is considered a critical event in metazoan embryogenesis as well as in physiological processes such as wound healing. However, it also plays an important role in pathological settings such as fibrotic disorders in various organs as well as cancer invasion and metastasis.The EMT associated with physiological processes is triggered by members of the transforming growth factor-␤ (TGF-␤) family of proteins that function as morphogens (1). In vitro studies have also shown that TGF-␤ is the major inducer of the EMT in epithelial cells (2). Fibrotic disorders associated with pathological EMT result from a series of events including inflammation, leukocyte infiltration, and the production of cytokines and growth factors. TGF-␤ is one of the cytokines produced during inflammation and is, therefore, thought to heavily contribute to EMT-associated fibrosis (3). However, given that TGF-␤ also possesses anti-inflammatory properties, the mechanism of pathological EMT induced by the inflammatory response may be multifactorial and differ from that of physiological EMT.In addition to growth factors, changes in the ECM microenvironment contribute to the EMT. Epithelial cells cultured in a type I collagen gel were found to undergo the EMT (4). Furthermore, collagen-induce...

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Section: Tnf-␣ Promotes the Formation Of Ha⅐cd44⅐permmentioning

confidence: 49%

Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction

Takahashi

Nagano

Ishimoto

et al. 2010

Journal of Biological Chemistry

146

150

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“…HA secretion is also stimulated by synovial mechanical distortion per se, as shown using sterile, non-pyrogenic infusions into un-inflamed joints (Coleman et al, 1997). Little is known, however, about the signal transduction pathway(s) mediating this response (Anggiansah et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

2006

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“…The presence of a latent form of endogenous HAS was suggested by experiments showing that protein kinase C activation stimulates hyaluronan synthesis partly through mechanisms independent of protein synthesis (30,31). Regulated mobilization of HAS from the Golgi complex would provide cells a way of responding to challenges that require rapid activation of hyaluronan synthesis.…”

Section: C-terminal Truncation Of Has3 and Exit From Er-mentioning

confidence: 99%

Plasma Membrane Residence of Hyaluronan Synthase Is Coupled to Its Enzymatic Activity

Rilla

Siiskonen

Spicer

et al. 2005

Journal of Biological Chemistry

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Hyaluronan is a multifunctional glycosaminoglycan up to 10 7 Da molecular mass produced by the integral membrane glycosyltransferase, hyaluronan synthase (HAS). When expressed in keratinocytes, N-terminally tagged green fluorescent protein-HAS2 and -HAS3 isoenzymes were found to travel through endoplasmic reticulum (ER), Golgi, plasma membrane, and endocytic vesicles. A distinct enrichment of plasma membrane HAS was found in cell protrusions. The total turnover time of HAS3 was 4 -5 h as judged by the green fluorescent protein signal decay and hyaluronan synthesis inhibition in cycloheximide-treated cells. The transfer from ER to Golgi took about 1 h, and the dwell time on the plasma membrane was less than 2 h in experiments with a relief and introduction, respectively, of brefeldin A. Constructs of HAS3 with 16-and 45-amino-acid C-terminal deletions mostly stayed within the ER, whereas a D216A missense mutant was localized within the Golgi complex but not the plasma membrane. Both types of mutations were almost or completely inactive, similar to the wild type enzyme that had its entry to the plasma membrane experimentally blocked by brefeldin A. Inhibition of hyaluronan synthesis by UDP-glucuronic acid starvation using 4-methyl-umbelliferone also prevented HAS access to the plasma membrane. The results demonstrate that 1) a latent pool of HAS exists within the ER-Golgi pathway; 2) this pool can be rapidly mobilized and activated by insertion into the plasma membrane; and 3) inhibition of HAS activity through mutation or substrate starvation results in exclusion of HAS from the plasma membrane.

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Regulation of hyaluronan secretion into rabbit synovial joints in vivo by protein kinase C

Cited by 21 publications

References 47 publications

Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction

Tumor Necrosis Factor-α Regulates Transforming Growth Factor-β-dependent Epithelial-Mesenchymal Transition by Promoting Hyaluronan-CD44-Moesin Interaction

Mechanosensitive synoviocytes: A Ca2+–PKCα–MAP kinase pathway contributes to stretch-induced hyaluronan synthesis in vitro

Plasma Membrane Residence of Hyaluronan Synthase Is Coupled to Its Enzymatic Activity

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