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.

Basic information

Original name

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

Authors

SALAŠOVÁ, Alena (203 Czech Republic), C. YOKOTA (752 Sweden), David POTĚŠIL (203 Czech Republic, belonging to the institution), Zbyněk ZDRÁHAL (203 Czech Republic, belonging to the institution), Vítězslav BRYJA (203 Czech Republic, guarantor, belonging to the institution) and E. ARENAS (752 Sweden)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30210 Clinical neurology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 6.426

RIV identification code

RIV/00216224:14310/17:00094936

Organization unit

Faculty of Science

DOI

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

UT WoS

000405188900001

Keywords in English

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

Abstract

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.

Links

GBP206/12/G151, research and development project

Name: Centrum nových přístupů k bioanalýze a molekulární diagnostice

LM2015043, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii (Acronym: CIISB)

Investor: Ministry of Education, Youth and Sports of the CR

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

Citovat

SALAŠOVÁ, Alena, C. YOKOTA, David POTĚŠIL, Zbyněk ZDRÁHAL, Vítězslav BRYJA and 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, vol. 12, No 54, p. 1-19. ISSN 1750-1326. Available from: 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 and 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, vol.~12, No~54, p.~1-19. ISSN~1750-1326. Available from: https://dx.doi.org/10.1186/s13024-017-0193-9.

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