Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor.
It is well established that acute activation of members of the protein kinase C (PKC) family induced by activation of cellular receptors can transduce extracellular stimuli to intracellular signaling. However, the functions of sustained activation of PKC are not well studied. We have previously show...
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doaj-8a1cf7d5ee7a45d592381db7f8e8d11f2020-11-25T01:00:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e8072110.1371/journal.pone.0080721Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor.Mengling LiuJolanta Idkowiak-BaldysPatrick L RoddyAleksander BaldysJohn RaymondChristopher J ClarkeYusuf A HannunIt is well established that acute activation of members of the protein kinase C (PKC) family induced by activation of cellular receptors can transduce extracellular stimuli to intracellular signaling. However, the functions of sustained activation of PKC are not well studied. We have previously shown that sustained activation of classical PKC isoforms over 15-60 min induced the formation of the pericentrion, a subset of recycling endosomes that are sequestered perinuclearly in a PKC- and phospholipase D (PLD)-dependent manner. In this study, we investigated the role of this process in the phosphorylation of EGFR on threonine 654 (Thr-654) and in the regulation of intracellular trafficking and fate of epidermal growth factor receptor (EGFR). Sustained stimulation of the angiotensin II receptor induced translocation of the EGFR to the pericentrion, which in turn prevents full access of EGF to the EGFR. These effects required PKC and PLD activities, and direct stimulation of PKC with phorbol esters was sufficient to reproduce these effects. Furthermore, activation of PKC induced delayed phosphorylation of EGFR on Thr-654 that coincided with the formation of the pericentrion and which was dependent on PLD and endocytosis of EGFR. Thus, Thr-654 phosphorylation required the formation of the pericentrion. On the other hand, using a T654A mutant of EGFR, we find that the phosphorylation on Thr-654 was not required for translocation of EGFR to the pericentrion but was required for protection of EGFR from degradation in response to EGF. Taken together, these results demonstrate a novel role for the pericentrion in the regulation of EGFR phosphorylation, which in turn is important for the fates of EGFR.http://europepmc.org/articles/PMC3823608?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mengling Liu Jolanta Idkowiak-Baldys Patrick L Roddy Aleksander Baldys John Raymond Christopher J Clarke Yusuf A Hannun |
spellingShingle |
Mengling Liu Jolanta Idkowiak-Baldys Patrick L Roddy Aleksander Baldys John Raymond Christopher J Clarke Yusuf A Hannun Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. PLoS ONE |
author_facet |
Mengling Liu Jolanta Idkowiak-Baldys Patrick L Roddy Aleksander Baldys John Raymond Christopher J Clarke Yusuf A Hannun |
author_sort |
Mengling Liu |
title |
Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
title_short |
Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
title_full |
Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
title_fullStr |
Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
title_full_unstemmed |
Sustained activation of protein kinase C induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
title_sort |
sustained activation of protein kinase c induces delayed phosphorylation and regulates the fate of epidermal growth factor receptor. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2013-01-01 |
description |
It is well established that acute activation of members of the protein kinase C (PKC) family induced by activation of cellular receptors can transduce extracellular stimuli to intracellular signaling. However, the functions of sustained activation of PKC are not well studied. We have previously shown that sustained activation of classical PKC isoforms over 15-60 min induced the formation of the pericentrion, a subset of recycling endosomes that are sequestered perinuclearly in a PKC- and phospholipase D (PLD)-dependent manner. In this study, we investigated the role of this process in the phosphorylation of EGFR on threonine 654 (Thr-654) and in the regulation of intracellular trafficking and fate of epidermal growth factor receptor (EGFR). Sustained stimulation of the angiotensin II receptor induced translocation of the EGFR to the pericentrion, which in turn prevents full access of EGF to the EGFR. These effects required PKC and PLD activities, and direct stimulation of PKC with phorbol esters was sufficient to reproduce these effects. Furthermore, activation of PKC induced delayed phosphorylation of EGFR on Thr-654 that coincided with the formation of the pericentrion and which was dependent on PLD and endocytosis of EGFR. Thus, Thr-654 phosphorylation required the formation of the pericentrion. On the other hand, using a T654A mutant of EGFR, we find that the phosphorylation on Thr-654 was not required for translocation of EGFR to the pericentrion but was required for protection of EGFR from degradation in response to EGF. Taken together, these results demonstrate a novel role for the pericentrion in the regulation of EGFR phosphorylation, which in turn is important for the fates of EGFR. |
url |
http://europepmc.org/articles/PMC3823608?pdf=render |
work_keys_str_mv |
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