Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

Hossain, Mohammad Zakir; Jagdale, Ajit B.; Ao, Ping; Kazlauskas, Andrius; Boynton, Alton L.

doi:10.1074/jbc.274.15.10489

Cited by 58 publications

(41 citation statements)

References 78 publications

(97 reference statements)

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“…These reductions were reflected in significant losses of Cx43 protein at cellular borders. Such findings are especially interesting in the light of suggestions by previous workers that activation of the ERK signalling pathway leads to hyperphosphorylation of Cx43 and that this in turn leads to reductions in GJIC (Hossain et al, 1998a;Hossain et al, 1999b;Kanemitsu and Lau, 1993;Warn-Cramer et al, 1998;Warn-Cramer et al, 1996).…”

Section: Discussionmentioning

confidence: 81%

Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathway

Ogawa

Hayashi

Kyoizumi

et al. 2004

Journal of Cell Science

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Phosphorylation of connexin 43 (Cx43) molecules (e.g. by extracellular signal-regulated kinase) leads to reductions in gap-junctional intercellular communication (GJIC). GJIC levels also appear to be lower in the presence of p38 mitogen-activated protein (MAP) kinase, for unknown reasons. In this study, we used assays of the recovery of fluorescence by photobleached WB-F344 cells to demonstrate that GJIC levels are decreased by anisomycin [a protein synthesis inhibitor as well as an activator of p38 MAP kinase and c-Jun N-terminal kinases (JNK)] as a result of time-dependent depletion of the phosphorylated forms of Cx43. Using immunohistochemistry, we also detected far less of the Cx43 proteins at cell borders. These findings agree with the photobleaching assay results. Moreover, prior treatment with SB203580 (a specific inhibitor of p38 MAP kinase) appeared to be effective in preventing the loss of phosphorylated forms of Cx43 and the loss of Cx43 proteins at cell borders. Total protein labelling with [35S]-methionine and [32P]-orthophosphates labelling of Cx43 showed that anisomycin enhanced the phosphorylation level of Cx43 along with inhibition of protein synthesis. SB203580 prevented the former but not the latter. The effect of anisomycin on GJIC was not dependent on the inhibition of protein synthesis because the addition of SB203580 completely maintained the level of GJIC without restoring protein synthesis. The Cx43 phosphorylation level increased by anisomycin treatment, whereas the amount of phosphorylated forms of Cx43 decreased, suggesting that activation of Cx43 phosphorylation might lead to the loss of Cx43. These results suggest that activation of p38 MAP kinase leads to reduction in the levels of phosphorylated forms of Cx43, possibly owing to accelerated degradation, and that these losses might be responsible for the reduction in numbers of gap junctions and in GJIC.

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Section: Discussionmentioning

confidence: 81%

Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathway

Ogawa

Hayashi

Kyoizumi

et al. 2004

Journal of Cell Science

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“…The synergistic action of PDGF-BB and cAMP-elevating agents on Cx43 expression and GJIC was unexpected, because PDGF-BB has been described as a potent inhibitor of GJIC (14,15,40). Counteracting effects between PDGF-BB and cAMP-elevating agents in the control of cell growth, migration, and other cell behaviors have been extensively documented (18,21,26), whereas little is known about the synergism between PDGF-BB and cAMP.…”

Section: Discussionmentioning

confidence: 99%

“…PKC is another important molecule implicated in the disruption of GJIC by PDGF-BB (14,15). To explore the role of PKC in our system, we assessed Cx43 expression in the presence of the PKC inhibitor calphostin C or under conditions of depletion of PKC by pretreatment with 12-O-tetradecanoylphorbol 13-acetate (10 Ϫ6 M) for 24 h (14).…”

Section: Potentiating Effect Of Pdgf-bb On Cx43 Expression Is Mediatementioning

confidence: 99%

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Synergistic effects of PDGF-BB and cAMP-elevating agents on expression of connexin43 in mesangial cells

Yao

Kitamura²,

Zhu³

et al. 2006

American Journal of Physiology-Renal Physiology

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The gap junction plays an important role in the regulation of cell growth, migration, and differentiation. Platelet-derived growth factor (PDGF) is reported to be a potent inhibitor of gap junctional intercellular communication (GJIC). Short-term exposure of cells to PDGF causes rapid and transient disruption of GJIC without altering connexin43 (Cx43) protein level. In this study, we investigated long-term effects of PDGF-BB on Cx43 expression in mesangial cells (MCs). Exposure of MCs to PDGF-BB affected neither the Cx43 protein level nor GJIC. However, in the presence of cAMP-elevating agents, PDGF-BB dramatically increased the expression of Cx43, which was accompanied by obviously augmented membrane distribution of Cx43 and functional GJIC. The increased expression of Cx43 was closely correlated with reduction in α-actin, a dedifferentiation marker of MCs. The effect of PDGF on Cx43 was largely prevented by inhibitors of phosphatidylinositol 3′-kinase or mitogen-activated protein kinase, but not by inhibition of protein kinase C. Exposure of MCs to PDGF-BB caused elevation in intracellular cAMP, and it was abolished by indomethacin, a cyclooxygenase inhibitor. However, indomethacin did not affect the synergistic effect. In addition, PDGF-BB also did not affect the degradation of Cx43. With the use of MCs transfected with a Cx43 promoter-luciferase vector, cooperative activation of Cx43 promoter by PDGF and cAMP was found. Together, our data reveal, for the first time, unexpected synergy between PDGF-BB and cAMP-elevating agents in the induction of Cx43 and MC differentiation. Regulation of GJIC could be an important mechanism via which PDGF modulates MC phenotypes.

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“…A number of potential consensus sites for both serine/threonine and tyrosine kinases can be identified. Detailed biochemical studies have shown that Cx43 acts as a substrate for phosphorylation by v-Src (7,8), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) (9)(10)(11). Recent evidence also suggests that Cx43 was phosphorylated by the mitosis-associated cdc-2 kinase (12) and cGMP-dependent phosphorylation of rat Cx43 has also been demonstrated (13).…”

Section: Introductionmentioning

confidence: 99%

Identification of a protein kinase activity that phosphorylates connexin43 in a pH-dependent manner

Yahuaca

Ek‐Vitorín

Rush

et al. 2000

Braz J Med Biol Res

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The carboxyl-terminal (CT) domain of connexin43 (Cx43) has been implicated in both hormonal and pH-dependent gating of the gap junction channel. An in vitro assay was utilized to determine whether the acidification of cell extracts results in the activation of a protein kinase that can phosphorylate the CT domain. A glutathione Stransferase (GST)-fusion protein was bound to Sephadex beads and used as a target for protein kinase phosphorylation. A protein extract produced from sheep heart was allowed to bind to the fusion proteincoated beads. The bound proteins were washed and then incubated with 32 P-ATP. Phosphorylation was assessed after the proteins were resolved by SDS-PAGE. Incubation at pH 7.5 resulted in a minimal amount of phosphorylation while incubation at pH 6.5 resulted in significant phosphorylation reaction. Maximal activity was achieved when both the binding and kinase reactions were performed at pH 6.5. The protein kinase activity was stronger when the incubations were performed with manganese rather than magnesium. Mutants of Cx43 which lack the serines between amino acids 364-374 could not be phosphorylated in the in vitro kinase reaction, indicating that this is a likely target of this reaction. These results indicate that there is a protein kinase activity in cells that becomes more active at lower pH and can phosphorylate Cx43. Correspondence

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Disruption of Gap Junctional Communication by the Platelet-derived Growth Factor Is Mediated via Multiple Signaling Pathways

Cited by 58 publications

References 78 publications

Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathway

Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathway

Synergistic effects of PDGF-BB and cAMP-elevating agents on expression of connexin43 in mesangial cells

Identification of a protein kinase activity that phosphorylates connexin43 in a pH-dependent manner

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