Cargando…
Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling
The dermonecrotic toxins from Pasteurella multocida (PMT), Bordetella (DNT), Escherichia coli (CNF1-3), and Yersinia (CNFY) modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downs...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2012
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417509/ https://www.ncbi.nlm.nih.gov/pubmed/22919671 http://dx.doi.org/10.3389/fcimb.2012.00080 |
_version_ | 1782240502782885888 |
---|---|
author | Bannai, Yuka Aminova, Leila R. Faulkner, Melinda J. Ho, Mengfei Wilson, Brenda A. |
author_facet | Bannai, Yuka Aminova, Leila R. Faulkner, Melinda J. Ho, Mengfei Wilson, Brenda A. |
author_sort | Bannai, Yuka |
collection | PubMed |
description | The dermonecrotic toxins from Pasteurella multocida (PMT), Bordetella (DNT), Escherichia coli (CNF1-3), and Yersinia (CNFY) modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downstream signaling pathways. Whereas DNT and the CNFs act on small Rho GTPases, PMT acts on the α subunit of heterotrimeric G(q), G(i), and G(12/13) proteins. We previously demonstrated that PMT potently blocks adipogenesis and adipocyte differentiation in a calcineurin-independent manner through downregulation of Notch1 and stabilization of β-catenin and Pref1/Dlk1, key proteins in signaling pathways strongly linked to cell fate decisions, including fat and bone development. Here, we report that similar to PMT, DNT, and CNF1 completely block adipogenesis and adipocyte differentiation by preventing upregulation of adipocyte markers, PPARγ and C/EBPα, while stabilizing the expression of Pref1/Dlk1 and β-catenin. We show that the Rho/ROCK inhibitor Y-27632 prevented or reversed these toxin-mediated effects, strongly supporting a role for Rho/ROCK signaling in dermonecrotic toxin-mediated inhibition of adipogenesis and adipocyte differentiation. Toxin treatment was also accompanied by downregulation of Notch1 expression, although this inhibition was independent of Rho/ROCK signaling. We further show that PMT-mediated downregulation of Notch1 expression occurs primarily through G(12/13) signaling. Our results reveal new details of the pathways involved in dermonecrotic toxin action on adipocyte differentiation, and the role of Rho/ROCK signaling in mediating toxin effects on Wnt/β-catenin and Notch1 signaling, and in particular the role of G(q) and G(12/13) in mediating PMT effects on Rho/ROCK and Notch1 signaling. |
format | Online Article Text |
id | pubmed-3417509 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-34175092012-08-23 Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling Bannai, Yuka Aminova, Leila R. Faulkner, Melinda J. Ho, Mengfei Wilson, Brenda A. Front Cell Infect Microbiol Microbiology The dermonecrotic toxins from Pasteurella multocida (PMT), Bordetella (DNT), Escherichia coli (CNF1-3), and Yersinia (CNFY) modulate their G-protein targets through deamidation and/or transglutamination of an active site Gln residue, which results in activation of the G protein and its cognate downstream signaling pathways. Whereas DNT and the CNFs act on small Rho GTPases, PMT acts on the α subunit of heterotrimeric G(q), G(i), and G(12/13) proteins. We previously demonstrated that PMT potently blocks adipogenesis and adipocyte differentiation in a calcineurin-independent manner through downregulation of Notch1 and stabilization of β-catenin and Pref1/Dlk1, key proteins in signaling pathways strongly linked to cell fate decisions, including fat and bone development. Here, we report that similar to PMT, DNT, and CNF1 completely block adipogenesis and adipocyte differentiation by preventing upregulation of adipocyte markers, PPARγ and C/EBPα, while stabilizing the expression of Pref1/Dlk1 and β-catenin. We show that the Rho/ROCK inhibitor Y-27632 prevented or reversed these toxin-mediated effects, strongly supporting a role for Rho/ROCK signaling in dermonecrotic toxin-mediated inhibition of adipogenesis and adipocyte differentiation. Toxin treatment was also accompanied by downregulation of Notch1 expression, although this inhibition was independent of Rho/ROCK signaling. We further show that PMT-mediated downregulation of Notch1 expression occurs primarily through G(12/13) signaling. Our results reveal new details of the pathways involved in dermonecrotic toxin action on adipocyte differentiation, and the role of Rho/ROCK signaling in mediating toxin effects on Wnt/β-catenin and Notch1 signaling, and in particular the role of G(q) and G(12/13) in mediating PMT effects on Rho/ROCK and Notch1 signaling. Frontiers Media S.A. 2012-06-05 /pmc/articles/PMC3417509/ /pubmed/22919671 http://dx.doi.org/10.3389/fcimb.2012.00080 Text en Copyright © 2012 Bannai, Aminova, Faulkner, Ho and Wilson. http://www.frontiersin.org/licenseagreement This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited. |
spellingShingle | Microbiology Bannai, Yuka Aminova, Leila R. Faulkner, Melinda J. Ho, Mengfei Wilson, Brenda A. Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title | Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title_full | Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title_fullStr | Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title_full_unstemmed | Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title_short | Rho/ROCK-dependent inhibition of 3T3-L1 adipogenesis by G-protein-deamidating dermonecrotic toxins: differential regulation of Notch1, Pref1/Dlk1, and β-catenin signaling |
title_sort | rho/rock-dependent inhibition of 3t3-l1 adipogenesis by g-protein-deamidating dermonecrotic toxins: differential regulation of notch1, pref1/dlk1, and β-catenin signaling |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417509/ https://www.ncbi.nlm.nih.gov/pubmed/22919671 http://dx.doi.org/10.3389/fcimb.2012.00080 |
work_keys_str_mv | AT bannaiyuka rhorockdependentinhibitionof3t3l1adipogenesisbygproteindeamidatingdermonecrotictoxinsdifferentialregulationofnotch1pref1dlk1andbcateninsignaling AT aminovaleilar rhorockdependentinhibitionof3t3l1adipogenesisbygproteindeamidatingdermonecrotictoxinsdifferentialregulationofnotch1pref1dlk1andbcateninsignaling AT faulknermelindaj rhorockdependentinhibitionof3t3l1adipogenesisbygproteindeamidatingdermonecrotictoxinsdifferentialregulationofnotch1pref1dlk1andbcateninsignaling AT homengfei rhorockdependentinhibitionof3t3l1adipogenesisbygproteindeamidatingdermonecrotictoxinsdifferentialregulationofnotch1pref1dlk1andbcateninsignaling AT wilsonbrendaa rhorockdependentinhibitionof3t3l1adipogenesisbygproteindeamidatingdermonecrotictoxinsdifferentialregulationofnotch1pref1dlk1andbcateninsignaling |