FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells

Abstract FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are f...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kouhei Yamawaki, Isamu Shiina, Takatsugu Murata, Satoru Tateyama, Yutarou Maekawa, Mariko Niwa, Motoyuki Shimonaka, Koji Okamoto, Toshihiro Suzuki, Toshirou Nishida, Ryo Abe, Yuuki Obata
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2a9ac2dd3360474c92df8bbb4d4fd572
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2a9ac2dd3360474c92df8bbb4d4fd572
record_format	dspace
spelling	oai:doaj.org-article:2a9ac2dd3360474c92df8bbb4d4fd5722021-11-28T12:16:54ZFLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells10.1038/s41598-021-02221-22045-2322https://doaj.org/article/2a9ac2dd3360474c92df8bbb4d4fd5722021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02221-2https://doaj.org/toc/2045-2322Abstract FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30–40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.Kouhei YamawakiIsamu ShiinaTakatsugu MurataSatoru TateyamaYutarou MaekawaMariko NiwaMotoyuki ShimonakaKoji OkamotoToshihiro SuzukiToshirou NishidaRyo AbeYuuki ObataNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kouhei Yamawaki Isamu Shiina Takatsugu Murata Satoru Tateyama Yutarou Maekawa Mariko Niwa Motoyuki Shimonaka Koji Okamoto Toshihiro Suzuki Toshirou Nishida Ryo Abe Yuuki Obata FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
description	Abstract FMS-like tyrosine kinase 3 (FLT3) in hematopoietic cells binds to its ligand at the plasma membrane (PM), then transduces growth signals. FLT3 gene alterations that lead the kinase to assume its permanently active form, such as internal tandem duplication (ITD) and D835Y substitution, are found in 30–40% of acute myelogenous leukemia (AML) patients. Thus, drugs for molecular targeting of FLT3 mutants have been developed for the treatment of AML. Several groups have reported that compared with wild-type FLT3 (FLT3-wt), FLT3 mutants are retained in organelles, resulting in low levels of PM localization of the receptor. However, the precise subcellular localization of mutant FLT3 remains unclear, and the relationship between oncogenic signaling and the mislocalization is not completely understood. In this study, we show that in cell lines established from leukemia patients, endogenous FLT3-ITD but not FLT3-wt clearly accumulates in the perinuclear region. Our co-immunofluorescence assays demonstrate that Golgi markers are co-localized with the perinuclear region, indicating that FLT3-ITD mainly localizes to the Golgi region in AML cells. FLT3-ITD biosynthetically traffics to the Golgi apparatus and remains there in a manner dependent on its tyrosine kinase activity. Tyrosine kinase inhibitors, such as quizartinib (AC220) and midostaurin (PKC412), markedly decrease FLT3-ITD retention and increase PM levels of the mutant. FLT3-ITD activates downstream in the endoplasmic reticulum (ER) and the Golgi apparatus during its biosynthetic trafficking. Results of our trafficking inhibitor treatment assays show that FLT3-ITD in the ER activates STAT5, whereas that in the Golgi can cause the activation of AKT and ERK. We provide evidence that FLT3-ITD signals from the early secretory compartments before reaching the PM in AML cells.
format	article
author	Kouhei Yamawaki Isamu Shiina Takatsugu Murata Satoru Tateyama Yutarou Maekawa Mariko Niwa Motoyuki Shimonaka Koji Okamoto Toshihiro Suzuki Toshirou Nishida Ryo Abe Yuuki Obata
author_facet	Kouhei Yamawaki Isamu Shiina Takatsugu Murata Satoru Tateyama Yutarou Maekawa Mariko Niwa Motoyuki Shimonaka Koji Okamoto Toshihiro Suzuki Toshirou Nishida Ryo Abe Yuuki Obata
author_sort	Kouhei Yamawaki
title	FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
title_short	FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
title_full	FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
title_fullStr	FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
title_full_unstemmed	FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
title_sort	flt3-itd transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2a9ac2dd3360474c92df8bbb4d4fd572
work_keys_str_mv	AT kouheiyamawaki flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT isamushiina flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT takatsugumurata flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT satorutateyama flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT yutaroumaekawa flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT marikoniwa flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT motoyukishimonaka flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT kojiokamoto flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT toshihirosuzuki flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT toshirounishida flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT ryoabe flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells AT yuukiobata flt3itdtransducesautonomousgrowthsignalsduringitsbiosynthetictraffickinginacutemyelogenousleukemiacells
_version_	1718408066590834688

FLT3-ITD transduces autonomous growth signals during its biosynthetic trafficking in acute myelogenous leukemia cells

Ejemplares similares