Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.

The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs), DOCK2 mediates the GTP-GDP exchange reaction for R...

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Autores principales:	Masao Terasawa, Takehito Uruno, Sayako Mori, Mutsuko Kukimoto-Niino, Akihiko Nishikimi, Fumiyuki Sanematsu, Yoshihiko Tanaka, Shigeyuki Yokoyama, Yoshinori Fukui
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9e2daa3ccf404236a26ed863bf8625c5
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spelling	oai:doaj.org-article:9e2daa3ccf404236a26ed863bf8625c52021-11-18T08:13:49ZDimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.1932-620310.1371/journal.pone.0046277https://doaj.org/article/9e2daa3ccf404236a26ed863bf8625c52012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23050005/?tool=EBIhttps://doaj.org/toc/1932-6203The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs), DOCK2 mediates the GTP-GDP exchange reaction for Rac via its DOCK homology region (DHR)-2 (also known as CZH2 or Docker) domain. DOCK2 DHR-2 domain is composed of three lobes, and Rac binding site and catalytic center are generated entirely from lobes B and C. On the other hand, lobe A has been implicated in dimer formation, yet its physiological significance remains unknown. Here, we report that lobe A-mediated DOCK2 dimerization is crucial for Rac activation and lymphocyte migration. We found that unlike wild-type DOCK2, DOCK2 mutant lacking lobe A failed to restore motility and polarity when expressed in thymoma cells and primary T cells lacking endogenous expression of DOCK2. Similar results were obtained with the DOCK2 point mutant having a defect in dimerization. Deletion of lobe A from the DHR-2 domain did not affect Rac GEF activity in vitro. However, fluorescence resonance energy transfer analyses revealed that lobe A is required for DOCK2 to activate Rac effectively during cell migration. Our results thus indicate that DOCK2 dimerization is functionally important under the physiological condition where only limited amounts of DOCK2 and Rac are localized to the plasma membrane.Masao TerasawaTakehito UrunoSayako MoriMutsuko Kukimoto-NiinoAkihiko NishikimiFumiyuki SanematsuYoshihiko TanakaShigeyuki YokoyamaYoshinori FukuiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 9, p e46277 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masao Terasawa Takehito Uruno Sayako Mori Mutsuko Kukimoto-Niino Akihiko Nishikimi Fumiyuki Sanematsu Yoshihiko Tanaka Shigeyuki Yokoyama Yoshinori Fukui Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
description	The migratory properties of lymphocytes depend on DOCK2, an atypical Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 does not contain the Dbl homology domain typically found in guanine nucleotide exchange factors (GEFs), DOCK2 mediates the GTP-GDP exchange reaction for Rac via its DOCK homology region (DHR)-2 (also known as CZH2 or Docker) domain. DOCK2 DHR-2 domain is composed of three lobes, and Rac binding site and catalytic center are generated entirely from lobes B and C. On the other hand, lobe A has been implicated in dimer formation, yet its physiological significance remains unknown. Here, we report that lobe A-mediated DOCK2 dimerization is crucial for Rac activation and lymphocyte migration. We found that unlike wild-type DOCK2, DOCK2 mutant lacking lobe A failed to restore motility and polarity when expressed in thymoma cells and primary T cells lacking endogenous expression of DOCK2. Similar results were obtained with the DOCK2 point mutant having a defect in dimerization. Deletion of lobe A from the DHR-2 domain did not affect Rac GEF activity in vitro. However, fluorescence resonance energy transfer analyses revealed that lobe A is required for DOCK2 to activate Rac effectively during cell migration. Our results thus indicate that DOCK2 dimerization is functionally important under the physiological condition where only limited amounts of DOCK2 and Rac are localized to the plasma membrane.
format	article
author	Masao Terasawa Takehito Uruno Sayako Mori Mutsuko Kukimoto-Niino Akihiko Nishikimi Fumiyuki Sanematsu Yoshihiko Tanaka Shigeyuki Yokoyama Yoshinori Fukui
author_facet	Masao Terasawa Takehito Uruno Sayako Mori Mutsuko Kukimoto-Niino Akihiko Nishikimi Fumiyuki Sanematsu Yoshihiko Tanaka Shigeyuki Yokoyama Yoshinori Fukui
author_sort	Masao Terasawa
title	Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
title_short	Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
title_full	Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
title_fullStr	Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
title_full_unstemmed	Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.
title_sort	dimerization of dock2 is essential for dock2-mediated rac activation and lymphocyte migration.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/9e2daa3ccf404236a26ed863bf8625c5
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Dimerization of DOCK2 is essential for DOCK2-mediated Rac activation and lymphocyte migration.

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