A proteomic analysis of LRRK2 binding partners reveals
interactions with multiple signaling components of the WNT/PCP
pathway

J 2017

A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway

SALAŠOVÁ, Alena; C. YOKOTA; David POTĚŠIL; Zbyněk ZDRÁHAL; Vítězslav BRYJA et. al.

Základní údaje

Originální název

A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway

Autoři

SALAŠOVÁ, Alena (203 Česká republika); C. YOKOTA (752 Švédsko); David POTĚŠIL (203 Česká republika, domácí); Zbyněk ZDRÁHAL (203 Česká republika, domácí); Vítězslav BRYJA (203 Česká republika, garant, domácí) a E. ARENAS (752 Švédsko)

Vydání

MOLECULAR NEURODEGENERATION, LONDON, BIOMED CENTRAL LTD, 2017, 1750-1326

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30210 Clinical neurology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 6.426

Kód RIV

RIV/00216224:14310/17:00094936

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1186/s13024-017-0193-9

UT WoS

000405188900001

EID Scopus

2-s2.0-85022190662

Klíčová slova anglicky

WNT/planar cell polarity; PRICKLE1; CELSR1; DVL; Parkinson's disease; Dopaminergic neurons; Substantia nigra; Immunoprecipitation; Endocytosis; Signalosomes

Štítky

CF PROT, NZ, OA, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 2. 3. 2018 09:13, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Background: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/beta-catenin signaling via its interaction with the beta-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Methods: Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/beta-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Results: Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/beta-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and beta-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/beta-catenin pathway, but induces a classical WNT/PCP phenotype in vivo.

Návaznosti

GBP206/12/G151, projekt VaV

Název: Centrum nových přístupů k bioanalýze a molekulární diagnostice

LM2015043, projekt VaV

Název: Česká infrastruktura pro integrativní strukturní biologii (Akronym: CIISB)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Czech Infrastructure for Integrative Structural Biology

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

SALAŠOVÁ, Alena; C. YOKOTA; David POTĚŠIL; Zbyněk ZDRÁHAL; Vítězslav BRYJA a E. ARENAS. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway. MOLECULAR NEURODEGENERATION. LONDON: BIOMED CENTRAL LTD, 2017, roč. 12, č. 54, s. 1-19. ISSN 1750-1326. Dostupné z: https://dx.doi.org/10.1186/s13024-017-0193-9.

@article{1389342,
   author = {Salašová, Alena and Yokota, C. and Potěšil, David and Zdráhal, Zbyněk and Bryja, Vítězslav and Arenas, E.},
   article_location = {LONDON},
   article_number = {54},
   doi = {http://dx.doi.org/10.1186/s13024-017-0193-9},
   keywords = {WNT/planar cell polarity; PRICKLE1; CELSR1; DVL; Parkinson's disease; Dopaminergic neurons; Substantia nigra; Immunoprecipitation; Endocytosis; Signalosomes},
   language = {eng},
   issn = {1750-1326},
   journal = {MOLECULAR NEURODEGENERATION},
   title = {A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway},
   volume = {12},
   year = {2017}
}

TY  - JOUR
ID  - 1389342
AU  - Salašová, Alena - Yokota, C. - Potěšil, David - Zdráhal, Zbyněk - Bryja, Vítězslav - Arenas, E.
PY  - 2017
TI  - A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway
JF  - MOLECULAR NEURODEGENERATION
VL  - 12
IS  - 54
SP  - 1-19
EP  - 1-19
PB  - BIOMED CENTRAL LTD
SN  - 17501326
KW  - WNT/planar cell polarity
KW  - PRICKLE1
KW  - CELSR1
KW  - DVL
KW  - Parkinson's disease
KW  - Dopaminergic neurons
KW  - Substantia nigra
KW  - Immunoprecipitation
KW  - Endocytosis
KW  - Signalosomes
N2  - Background: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/beta-catenin signaling via its interaction with the beta-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Methods: Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/beta-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Results: Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/beta-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and beta-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/beta-catenin pathway, but induces a classical WNT/PCP phenotype in vivo.
ER  -

SALAŠOVÁ, Alena; C. YOKOTA; David POTĚŠIL; Zbyněk ZDRÁHAL; Vítězslav BRYJA a E. ARENAS. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway. \textit{MOLECULAR NEURODEGENERATION}. LONDON: BIOMED CENTRAL LTD, 2017, roč.~12, č.~54, s.~1-19. ISSN~1750-1326. Dostupné z: https://dx.doi.org/10.1186/s13024-017-0193-9.

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