Cargando…

DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation

Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynami...

Descripción completa

Detalles Bibliográficos
Autores principales: Ogawa, Kana, Tanaka, Yoshihiko, Uruno, Takehito, Duan, Xuefeng, Harada, Yosuke, Sanematsu, Fumiyuki, Yamamura, Kazuhiko, Terasawa, Masao, Nishikimi, Akihiko, Côté, Jean-François, Fukui, Yoshinori
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076576/
https://www.ncbi.nlm.nih.gov/pubmed/24913231
http://dx.doi.org/10.1084/jem.20131926
_version_ 1782323500818628608
author Ogawa, Kana
Tanaka, Yoshihiko
Uruno, Takehito
Duan, Xuefeng
Harada, Yosuke
Sanematsu, Fumiyuki
Yamamura, Kazuhiko
Terasawa, Masao
Nishikimi, Akihiko
Côté, Jean-François
Fukui, Yoshinori
author_facet Ogawa, Kana
Tanaka, Yoshihiko
Uruno, Takehito
Duan, Xuefeng
Harada, Yosuke
Sanematsu, Fumiyuki
Yamamura, Kazuhiko
Terasawa, Masao
Nishikimi, Akihiko
Côté, Jean-François
Fukui, Yoshinori
author_sort Ogawa, Kana
collection PubMed
description Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5–Nck2–Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation.
format Online
Article
Text
id pubmed-4076576
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-40765762014-12-30 DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation Ogawa, Kana Tanaka, Yoshihiko Uruno, Takehito Duan, Xuefeng Harada, Yosuke Sanematsu, Fumiyuki Yamamura, Kazuhiko Terasawa, Masao Nishikimi, Akihiko Côté, Jean-François Fukui, Yoshinori J Exp Med Article Mast cells play a key role in the induction of anaphylaxis, a life-threatening IgE-dependent allergic reaction, by secreting chemical mediators that are stored in secretory granules. Degranulation of mast cells is triggered by aggregation of the high-affinity IgE receptor, FcεRI, and involves dynamic rearrangement of microtubules. Although much is known about proximal signals downstream of FcεRI, the distal signaling events controlling microtubule dynamics remain elusive. Here we report that DOCK5, an atypical guanine nucleotide exchange factor (GEF) for Rac, is essential for mast cell degranulation. As such, we found that DOCK5-deficient mice exhibit resistance to systemic and cutaneous anaphylaxis. The Rac GEF activity of DOCK5 is surprisingly not required for mast cell degranulation. Instead, DOCK5 associated with Nck2 and Akt to regulate microtubule dynamics through phosphorylation and inactivation of GSK3β. When DOCK5–Nck2–Akt interactions were disrupted, microtubule formation and degranulation response were severely impaired. Our results thus identify DOCK5 as a key signaling adaptor that orchestrates remodeling of the microtubule network essential for mast cell degranulation. The Rockefeller University Press 2014-06-30 /pmc/articles/PMC4076576/ /pubmed/24913231 http://dx.doi.org/10.1084/jem.20131926 Text en © 2014 Ogawa et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Ogawa, Kana
Tanaka, Yoshihiko
Uruno, Takehito
Duan, Xuefeng
Harada, Yosuke
Sanematsu, Fumiyuki
Yamamura, Kazuhiko
Terasawa, Masao
Nishikimi, Akihiko
Côté, Jean-François
Fukui, Yoshinori
DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title_full DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title_fullStr DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title_full_unstemmed DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title_short DOCK5 functions as a key signaling adaptor that links FcεRI signals to microtubule dynamics during mast cell degranulation
title_sort dock5 functions as a key signaling adaptor that links fcεri signals to microtubule dynamics during mast cell degranulation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076576/
https://www.ncbi.nlm.nih.gov/pubmed/24913231
http://dx.doi.org/10.1084/jem.20131926
work_keys_str_mv AT ogawakana dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT tanakayoshihiko dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT urunotakehito dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT duanxuefeng dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT haradayosuke dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT sanematsufumiyuki dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT yamamurakazuhiko dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT terasawamasao dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT nishikimiakihiko dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT cotejeanfrancois dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation
AT fukuiyoshinori dock5functionsasakeysignalingadaptorthatlinksfcerisignalstomicrotubuledynamicsduringmastcelldegranulation