Vangl2 interaction plays a role in the proteasomal degradation of Prickle2

Tadahiro Nagaoka, Mikio Furuse, Toshihisa Ohtsuka, Kunihiro Tsuchida, Masashi Kishi

Research output: Contribution to journalArticle

Abstract

The PET and LIM domain-containing protein, Prickle, plays a key role in planar cell polarity (PCP) in Drosophila. It has been reported that mutations in the PRICKLE2 gene, which encodes one of the human orthologues of Prickle, are associated with human diseases such as epilepsy and autism spectrum disorder. To develop preventive and therapeutic strategies for these intractable diseases, we studied the regulation of Prickle2 protein levels in transfected HEK293T cells. Prickle2 levels were negatively regulated by a physical interaction with another PCP protein, Van Gogh-like 2 (Vangl2). The Vangl2-mediated reduction in Prickle2 levels was, at least in part, relieved by proteasome inhibitors or by functional inhibition of the Cullin-1 E3 ubiquitin ligase. Furthermore, the expression of Vangl2 enhanced the polyubiquitination of Prickle2. This ubiquitination was partially blocked by co-expression of a ubiquitin mutant, which cannot be polymerised through their Lys48 residue to induce target proteins toward proteasomal degradation. Together, these results suggest that Prickle2 is polyubiquitinated by the Vangl2 interaction in a Cullin-1-dependent manner to limit its expression levels. This regulation may play a role in the local and temporal fine-tuning of Prickle protein levels during PCP signal-dependent cellular behaviours.

Original languageEnglish
Article number2912
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 01-12-2019

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Cell Polarity
Proteins
LIM Domain Proteins
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Ubiquitination
Ubiquitin
Drosophila
Epilepsy
Mutation
Genes
Cullin 1
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

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Nagaoka, Tadahiro ; Furuse, Mikio ; Ohtsuka, Toshihisa ; Tsuchida, Kunihiro ; Kishi, Masashi. / Vangl2 interaction plays a role in the proteasomal degradation of Prickle2. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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abstract = "The PET and LIM domain-containing protein, Prickle, plays a key role in planar cell polarity (PCP) in Drosophila. It has been reported that mutations in the PRICKLE2 gene, which encodes one of the human orthologues of Prickle, are associated with human diseases such as epilepsy and autism spectrum disorder. To develop preventive and therapeutic strategies for these intractable diseases, we studied the regulation of Prickle2 protein levels in transfected HEK293T cells. Prickle2 levels were negatively regulated by a physical interaction with another PCP protein, Van Gogh-like 2 (Vangl2). The Vangl2-mediated reduction in Prickle2 levels was, at least in part, relieved by proteasome inhibitors or by functional inhibition of the Cullin-1 E3 ubiquitin ligase. Furthermore, the expression of Vangl2 enhanced the polyubiquitination of Prickle2. This ubiquitination was partially blocked by co-expression of a ubiquitin mutant, which cannot be polymerised through their Lys48 residue to induce target proteins toward proteasomal degradation. Together, these results suggest that Prickle2 is polyubiquitinated by the Vangl2 interaction in a Cullin-1-dependent manner to limit its expression levels. This regulation may play a role in the local and temporal fine-tuning of Prickle protein levels during PCP signal-dependent cellular behaviours.",
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Vangl2 interaction plays a role in the proteasomal degradation of Prickle2. / Nagaoka, Tadahiro; Furuse, Mikio; Ohtsuka, Toshihisa; Tsuchida, Kunihiro; Kishi, Masashi.

In: Scientific Reports, Vol. 9, No. 1, 2912, 01.12.2019.

Research output: Contribution to journalArticle

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