Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment

Giovanna M. Collu, Andreas Jenny, Konstantin Gaengel, Ivana Mirkovic, Mei Ling Chin, Ursula Weber, Michael J. Smith, Marek Mlodzik

Research output: Contribution to journalArticle

Abstract

Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The ‘core’ PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pkpkbut not pkspleand enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

Original languageEnglish (US)
Article numbere1007391
JournalPLoS Genetics
Volume14
Issue number5
DOIs
StatePublished - May 1 2018

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Cell Polarity
plant spines
Leg
legs
Protein Isoforms
degradation
Diptera
Phosphorylation
positioning
eyes
Gene Components
defect
Homeodomain Proteins
photoreceptors
genome
fruit
membrane
phosphorylation
substrate
Protein Kinases

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. / Collu, Giovanna M.; Jenny, Andreas; Gaengel, Konstantin; Mirkovic, Ivana; Chin, Mei Ling; Weber, Ursula; Smith, Michael J.; Mlodzik, Marek.

In: PLoS Genetics, Vol. 14, No. 5, e1007391, 01.05.2018.

Research output: Contribution to journalArticle

Collu, Giovanna M. ; Jenny, Andreas ; Gaengel, Konstantin ; Mirkovic, Ivana ; Chin, Mei Ling ; Weber, Ursula ; Smith, Michael J. ; Mlodzik, Marek. / Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. In: PLoS Genetics. 2018 ; Vol. 14, No. 5.
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AU - Collu, Giovanna M.

AU - Jenny, Andreas

AU - Gaengel, Konstantin

AU - Mirkovic, Ivana

AU - Chin, Mei Ling

AU - Weber, Ursula

AU - Smith, Michael J.

AU - Mlodzik, Marek

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AB - Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The ‘core’ PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pkpkbut not pkspleand enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate.

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