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PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation.
Biosci Rep. 2008 Dec; 28(6):307-17.BR

Abstract

Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of G(alpha) and G(betagamma) heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-beta/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of 'conventional' PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCzeta by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCzeta inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCzeta in this process.

Authors+Show Affiliations

Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Apartado Postal 70-253, Ciudad Universitaria, C.P. 04510, México, D.F, Mexico.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18636965

Citation

Palma-Nicolas, Jose P., et al. "PKC Isoenzymes Differentially Modulate the Effect of Thrombin On MAPK-dependent RPE Proliferation." Bioscience Reports, vol. 28, no. 6, 2008, pp. 307-17.
Palma-Nicolas JP, López E, López-Colomé AM. PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation. Biosci Rep. 2008;28(6):307-17.
Palma-Nicolas, J. P., López, E., & López-Colomé, A. M. (2008). PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation. Bioscience Reports, 28(6), 307-17. https://doi.org/10.1042/BSR20080083
Palma-Nicolas JP, López E, López-Colomé AM. PKC Isoenzymes Differentially Modulate the Effect of Thrombin On MAPK-dependent RPE Proliferation. Biosci Rep. 2008;28(6):307-17. PubMed PMID: 18636965.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PKC isoenzymes differentially modulate the effect of thrombin on MAPK-dependent RPE proliferation. AU - Palma-Nicolas,Jose P, AU - López,Edith, AU - López-Colomé,Ana María, PY - 2008/7/19/pubmed PY - 2009/2/20/medline PY - 2008/7/19/entrez SP - 307 EP - 17 JF - Bioscience reports JO - Biosci. Rep. VL - 28 IS - 6 N2 - Thrombin signalling through PAR (protease-activated receptor)-1 is involved in cellular processes, such as proliferation, differentiation and cell survival. Following traumatic injury to the eye, thrombin signalling may participate in disorders, such as PVR (proliferative vitreoretinopathy), a human eye disease characterized by the uncontrolled proliferation, transdifferentiation and migration of otherwise quiescent RPE (retinal pigment epithelium) cells. PARs activate the Ras/Raf/MEK/ERK MAPK pathway (where ERK is extracellular-signal-regulated kinase, MAPK is mitogen-activated protein kinase and MEK is MAPK/ERK kinase) through the activation of G(alpha) and G(betagamma) heterotrimeric G-proteins, and the downstream stimulation of the PLC (phospholipase C)-beta/PKC (protein kinase C) and PI3K (phosphoinositide 3-kinase) signalling axis. In the present study, we examined the molecular signalling involved in thrombin-induced RPE cell proliferation, using rat RPE cells in culture as a model system for PVR pathogenesis. Our results showed that thrombin activation of PAR-1 induces RPE cell proliferation through Ras-independent activation of the Raf/MEK/ERK1/2 MAPK signalling cascade. Pharmacological analysis revealed that the activation of 'conventional' PKC isoforms is essential for proliferation, although thrombin-induced phosphorylation of ERK1/2 requires the activation of atypical PKCzeta by PI3K. Consistently, thrombin-induced ERK1/2 activation and RPE cell proliferation were prevented completely by PI3K or PKCzeta inhibition. These results suggest that thrombin induces RPE cell proliferation by joint activation of PLC-dependent and atypical PKC isoforms and the Ras-independent downstream stimulation of the Raf/MEK/ERK1/2 MAPK cascade. The present study is the first report demonstrating directly thrombin-induced ERK phosphorylation in the RPE, and the involvement of atypical PKCzeta in this process. SN - 0144-8463 UR - https://www.unboundmedicine.com/medline/citation/18636965/PKC_isoenzymes_differentially_modulate_the_effect_of_thrombin_on_MAPK_dependent_RPE_proliferation_ L2 - https://portlandpress.com/bioscirep/article-lookup/doi/10.1042/BSR20080083 DB - PRIME DP - Unbound Medicine ER -