LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells.
LAMTOR2 (p14), a part of the larger LAMTOR/Ragulator complex, plays a crucial role in EGF-dependent activation of p42/44 mitogen-activated protein kinases (MAPK, ERK1/2). In this study, we investigated the role of LAMTOR2 in nerve growth factor (NGF)-mediated neuronal differentiation. Stimulation of...
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2014
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oai:doaj.org-article:8237df9269a84107abcf61288544676a2021-11-18T08:22:05ZLAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells.1932-620310.1371/journal.pone.0095863https://doaj.org/article/8237df9269a84107abcf61288544676a2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24752675/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203LAMTOR2 (p14), a part of the larger LAMTOR/Ragulator complex, plays a crucial role in EGF-dependent activation of p42/44 mitogen-activated protein kinases (MAPK, ERK1/2). In this study, we investigated the role of LAMTOR2 in nerve growth factor (NGF)-mediated neuronal differentiation. Stimulation of PC12 (rat adrenal pheochromocytoma) cells with NGF is known to activate the MAPK. Pharmacological inhibition of MEK1 as well as siRNA-mediated knockdown of both p42 and p44 MAPK resulted in inhibition of neurite outgrowth. Contrary to expectations, siRNA-mediated knockdown of LAMTOR2 effectively augmented neurite formation and neurite length of PC12 cells. Ectopic expression of a siRNA-resistant LAMTOR2 ortholog reversed this phenotype back to wildtype levels, ruling out nonspecific off-target effects of this LAMTOR2 siRNA approach. Mechanistically, LAMTOR2 siRNA treatment significantly enhanced NGF-dependent MAPK activity, and this effect again was reversed upon expression of the siRNA-resistant LAMTOR2 ortholog. Studies of intracellular trafficking of the NGF receptor TrkA revealed a rapid colocalization with early endosomes, which was modulated by LAMTOR2 siRNA. Inhibition of LAMTOR2 and concomitant destabilization of the remaining members of the LAMTOR complex apparently leads to a faster release of the TrkA/MAPK signaling module and nuclear increase of activated MAPK. These results suggest a modulatory role of the MEK1 adapter protein LAMTOR2 in NGF-mediated MAPK activation required for induction of neurite outgrowth in PC12 cells.Bettina ThauererPaul VoegeleNatascha Hermann-KleiterNikolaus ThuilleMariana E G de AraujoMartin OffterdingerGottfried BaierLukas A HuberGabriele Baier-BitterlichPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e95863 (2014) |
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Medicine R Science Q Bettina Thauerer Paul Voegele Natascha Hermann-Kleiter Nikolaus Thuille Mariana E G de Araujo Martin Offterdinger Gottfried Baier Lukas A Huber Gabriele Baier-Bitterlich LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| description |
LAMTOR2 (p14), a part of the larger LAMTOR/Ragulator complex, plays a crucial role in EGF-dependent activation of p42/44 mitogen-activated protein kinases (MAPK, ERK1/2). In this study, we investigated the role of LAMTOR2 in nerve growth factor (NGF)-mediated neuronal differentiation. Stimulation of PC12 (rat adrenal pheochromocytoma) cells with NGF is known to activate the MAPK. Pharmacological inhibition of MEK1 as well as siRNA-mediated knockdown of both p42 and p44 MAPK resulted in inhibition of neurite outgrowth. Contrary to expectations, siRNA-mediated knockdown of LAMTOR2 effectively augmented neurite formation and neurite length of PC12 cells. Ectopic expression of a siRNA-resistant LAMTOR2 ortholog reversed this phenotype back to wildtype levels, ruling out nonspecific off-target effects of this LAMTOR2 siRNA approach. Mechanistically, LAMTOR2 siRNA treatment significantly enhanced NGF-dependent MAPK activity, and this effect again was reversed upon expression of the siRNA-resistant LAMTOR2 ortholog. Studies of intracellular trafficking of the NGF receptor TrkA revealed a rapid colocalization with early endosomes, which was modulated by LAMTOR2 siRNA. Inhibition of LAMTOR2 and concomitant destabilization of the remaining members of the LAMTOR complex apparently leads to a faster release of the TrkA/MAPK signaling module and nuclear increase of activated MAPK. These results suggest a modulatory role of the MEK1 adapter protein LAMTOR2 in NGF-mediated MAPK activation required for induction of neurite outgrowth in PC12 cells. |
| format |
article |
| author |
Bettina Thauerer Paul Voegele Natascha Hermann-Kleiter Nikolaus Thuille Mariana E G de Araujo Martin Offterdinger Gottfried Baier Lukas A Huber Gabriele Baier-Bitterlich |
| author_facet |
Bettina Thauerer Paul Voegele Natascha Hermann-Kleiter Nikolaus Thuille Mariana E G de Araujo Martin Offterdinger Gottfried Baier Lukas A Huber Gabriele Baier-Bitterlich |
| author_sort |
Bettina Thauerer |
| title |
LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| title_short |
LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| title_full |
LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| title_fullStr |
LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| title_full_unstemmed |
LAMTOR2-mediated modulation of NGF/MAPK activation kinetics during differentiation of PC12 cells. |
| title_sort |
lamtor2-mediated modulation of ngf/mapk activation kinetics during differentiation of pc12 cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/8237df9269a84107abcf61288544676a |
| work_keys_str_mv |
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| _version_ |
1718421869940441088 |