Modification of tight junction function by protein kinase C isoforms

Clarke, Hilary

doi:10.1016/s0169-409x(00)00047-8

Cited by 84 publications

(65 citation statements)

References 141 publications

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“…It is thought that a phosphorylation event contributes to the translocation of TJPs (Clarke et al, 2000;Farshori and Kachar, 1999;Hirase et al, 2001;Stamatovic et al, 2006;Stamatovic et al, 2003;Ward et al, 2002). The kinases responsible for the phosphorylation involve members of PKC family and Rhoassociated kinase (ROCK) Stamatovic et al, 2003), although it is not clear how phosphorylation of TJPs leads to their subcellular redistribution.…”

Section: Discussionmentioning

confidence: 99%

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Yao

Tsirka

2011

Journal of Cell Science

102

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SummaryPrevious studies have shown that plasmin cleaves monocyte chemoattractant protein 1 (MCP1; officially known as C-C motif chemokine 2, CCL2) at K104, and this cleavage enhances its chemotactic potency significantly. Accumulating evidence reveals that MCP1 also disrupts the integrity of the blood-brain barrier (BBB). Here, we show that K104Stop-MCP1, truncated at the K104 where plasmin would normally cleave, is more efficient than the full-length protein (FL-MCP1) in compromising the integrity of the BBB in in vitro and in vivo models. K104Stop-MCP1 increases the permeability of BBB in both wild-type mice and mice deficient for tissue plasminogen activator (tPA), which converts plasminogen into active plasmin, suggesting that plasmin-mediated truncation of MCP1 plays an important role in BBB compromise. Furthermore, we show that the mechanisms underlying MCP1-induced BBB disruption involve redistribution of tight junction proteins (occludin and ZO-1) and reorganization of the actin cytoskeleton. Finally, we show that the redistribution of ZO-1 is mediated by phosphorylation of ezrin-radixin-moesin (ERM) proteins. These findings identify plasmin as a key signaling molecule in the regulation of BBB integrity and suggest that plasmin inhibitors might be used to modulate diseases accompanied by BBB compromise.

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Section: Discussionmentioning

confidence: 99%

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Yao

Tsirka

2011

Journal of Cell Science

102

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“…These data are consistent with our finding that claudin-3 can be phosphorylated in vivo and the observation that this phosphorylation interferes with TJ function. Studies have implicated protein kinase C in the regulation of TJs through phorbol ester stimulation (17,34), but PKA-dependent regulation of TJs has been poorly documented and is more controversial (20). PKA activation has been suggested to have a role in TJ disruption (32), and claudin-3 phosphorylation may represent one of the targets to achieve this physiological outcome.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Claudin-3 at Threonine 192 by cAMP-dependent Protein Kinase Regulates Tight Junction Barrier Function in Ovarian Cancer Cells

D’Souza

Agarwal

Morin

2005

Journal of Biological Chemistry

194

147

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Claudins are integral membrane proteins essential in the formation and function of tight junctions (TJs). Disruption of TJs, which have essential roles in cell permeability and polarity, is thought to contribute to epithelial tumorigenesis. Claudin-3 and -4 are frequently overexpressed in ovarian cancer, but the molecular pathways involved in the regulation of these proteins are unclear. Interestingly, several studies have demonstrated a role for phosphorylation in the regulation of TJ complexes, although evidence for claudin phosphorylation is scarce. Here, we showed that claudin-3 and -4 can be phosphorylated in ovarian cancer cells. In vitro phosphorylation assays using glutathione S-transferase fusion constructs demonstrated that the C terminus of claudin-3 is an excellent substrate for cAMP-dependent protein kinase (PKA). Using site-directed mutagenesis, we identified a PKA phosphorylation site at amino acid 192 in the C terminus of claudin-3. Overexpression of the protein containing a T192D mutation, mimicking the phosphorylated state, resulted in a decrease in TJ strength in ovarian cancer cell line OVCA433. Our results suggest that claudin-3 phosphorylation by PKA, a kinase frequently activated in ovarian cancer, may provide a mechanism for the disruption of TJs in this cancer. In addition, our findings may have general implications for the regulation of TJs in normal epithelial cells.

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“…Numerous agents and cell signaling pathways interact with the TJ protein complex [21,22] and the involvement of kinases in the biogenesis and regulation of the TJ components is well established [23][24][25][26][27][28]. Interestingly, several studies have demonstrated the involvement of various kinases in the phosphorylation and regulation of claudin proteins [29][30][31][32][33][34][35][36][37], and we have recently shown that phosphorylation of claudin-3 by PKA can affect TJ properties in ovarian cancer cells [38].…”

Section: Introductionmentioning

confidence: 94%

“…Interestingly, several studies have demonstrated the involvement of various kinases in the phosphorylation and regulation of claudin proteins [29][30][31][32][33][34][35][36][37], and we have recently shown that phosphorylation of claudin-3 by PKA can affect TJ properties in ovarian cancer cells [38]. Protein kinase C (PKC) isoforms are present in ovarian cancer and are known to modulate TJ function by phosphorylation of the proteins in the complex [24,34,[39][40][41][42][43], but it is unclear whether PKC can directly phosphorylate and regulate claudin proteins. We have previously shown that claudin-4 can be phosphorylated in ovarian cancer cells upon 12-OTetradecanoylophorbol-13-acetate (TPA) stimulation [38], but the exact PKC isoforms involved, the phosphorylation sites on claudin-4, and the consequences of this phosphorylation have remained unknown.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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Claudin proteins belong to a large family of transmembrane proteins essential to the formation and maintenance of tight junctions (TJs). In ovarian cancer, TJ protein claudin-4 is frequently overexpressed and may have roles in survival and invasion, but the molecular mechanisms underlying its regulation are poorly understood. In this report, we show that claudin-4 can be phosphorylated by protein kinase C (PKC) at Thr189 and Ser194 in ovarian cancer cells and overexpression of a claudin-4 mutant protein mimicking the phosphorylated state results in the disruption of the barrier function. Furthermore, upon phorbol ester-mediated PKC activation of OVCA433 cells, TJ strength is decreased and claudin-4 localization is altered. Analyses using PKC inhibitors and siRNA suggest that PKCε, an isoform typically expressed in ovarian cancer cells, may be important in the TPAmediated claudin-4 phosphorylation and weakening of the TJs. Furthermore, immunofluorescence studies showed that claudin-4 and PKCε are co-localized at the TJs in these cells. The modulation of claudin-4 activity by PKCε may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells.

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Modification of tight junction function by protein kinase C isoforms

Cited by 84 publications

References 141 publications

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood–brain barrier disruption

Phosphorylation of Claudin-3 at Threonine 192 by cAMP-dependent Protein Kinase Regulates Tight Junction Barrier Function in Ovarian Cancer Cells

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

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