dGIPC is required for the locomotive activity and longevity in Drosophila

Kim, Jihyun; Lee, Soojeong; Ko, Sung-Kyun; Kim-Ha, Jeongsil

doi:10.1016/j.bbrc.2010.10.095

Cited by 12 publications

(11 citation statements)

References 29 publications

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“…Disruption of GIPC1 function leads to defects in hair cell maturation and hair follicle orientation, a typical phenotype displayed by WNT/PCP deregulation [21]. Moreover, it has been shown that GIPC1 interacts with dopamine D2 and D3 receptors [67–70] and its mutation results in a reduction of DA neurons leading to locomotion defects in D. melanogaster [71]. It is thus conceivable that alterations in the interaction between LRRK2 and GIPC1 may be of importance for the function of mDA neurons, a possibility that remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

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

Salašová

Yokota

Potěšil

et al. 2017

Mol Neurodegeneration

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BackgroundAutosomal-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/β-catenin signaling via its interaction with the β-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.MethodsCo-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/β-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.ResultsOur 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/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo.ConclusionsOur study shows for the first time that LRRK2 activates the WNT/PCP signaling pathway through its interaction to multiple WNT/PCP components. We suggest that LRRK2 regulates the balance between WNT/β-catenin and WNT/PCP signaling, depending on the binding partners. Since this balance is crucial for homeostasis of midbrain dopaminergic neurons, we hypothesize that its alteration may contribute to the pathophysiology of Parkinson’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0193-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

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

Salašová

Yokota

Potěšil

et al. 2017

Mol Neurodegeneration

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“…The Drosophila GIPC homolog, dGIPC, was first described in a gain-of-function screen designed to identify planar cell polarity genes in Drosophila (Djiane and Mlodzik, 2010). dGIPC is also important for locomotor activity and longevity, possibly through the regulation of dopamine (DA) receptor trafficking (Kim et al, 2010).…”

Section: Plexa Augments Cgmp Levels Produced By Gyc76c In Vitromentioning

confidence: 99%

“…dGIPC-null mutants display motor axon defects, and so dGIPC could function in neurons, non-neuronal cells, or both. In the Drosophila brain, dGIPC is predominantly expressed in glial cells but is also expressed in DA neurons, and DA neuronal expression of dGIPC is crucial for locomotor activity (Kim et al, 2010). To determine dGIPC cell type requirements, we employed Gal4 drivers for in vivo rescue experiments dGIPC ex31 homozygous mutant embryos.…”

Section: Plexa Augments Cgmp Levels Produced By Gyc76c In Vitromentioning

confidence: 99%

Function of theDrosophilareceptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance

Chak

Kolodkin

2014

Development

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The second messengers cAMP and cGMP modulate attraction and repulsion mediated by neuronal guidance cues. We find that the Drosophila receptor guanylyl cyclase Gyc76C genetically interacts with Semaphorin 1a (Sema-1a) and physically associates with the Sema-1a receptor plexin A (PlexA). PlexA regulates Gyc76C catalytic activity in vitro, and each distinct Gyc76C protein domain is crucial for regulating Gyc76C activity in vitro and motor axon guidance in vivo. The cytosolic protein dGIPC interacts with Gyc76C and facilitates Sema-1a-PlexA/Gyc76C-mediated motor axon guidance. These findings provide an in vivo link between semaphorin-mediated repulsive axon guidance and alteration of intracellular neuronal cGMP levels.

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“…1, 2, 3, 4, 16, 17, 18, 19, 20, 21, 22, 23, 24 GIPCs are involved in the trafficking of various transmembrane proteins and regulate a variety of cellular processes, such as proliferation, planar cell polarity, cytokinesis and migration. Pathologies associated with the GIPCs, such as hearing loss 11, 12 and cancer, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 are emerging topics in the medical sciences.…”

Section: Introductionmentioning

confidence: 99%

Functional proteomics, human genetics and cancer biology of GIPC family members

Katoh

2013

Exp Mol Med

123

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GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFβR3 (transforming growth factorβ receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin α5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFβR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K–AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Gα signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorβ signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness.

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dGIPC is required for the locomotive activity and longevity in Drosophila

Cited by 12 publications

References 29 publications

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

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

Function of theDrosophilareceptor guanylyl cyclase Gyc76C in PlexA-mediated motor axon guidance

Functional proteomics, human genetics and cancer biology of GIPC family members

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