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Four-jointed is a Golgi kinase that phosphorylates a subset of cadherin domains

Hiroyuki O Ishikawa1, Hideyuki Takeuchi, Robert S Haltiwanger

  • 1Howard Hughes Medical Institute, Waksman Institute and Department of Molecular Biology and Biochemistry, Rutgers University, Piscataway, NJ 08854, USA.

Science (New York, N.Y.)
|July 19, 2008
PubMed

Insights

The study identifies Four-jointed as a protein kinase that regulates Fat signaling by phosphorylating extracellular domains of Fat and Dachsous proteins. This kinase activity, essential for growth and planar cell polarity, occurs within the Golgi apparatus.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Background:

  • The atypical cadherin Fat is crucial for regulating cell growth, gene expression, and planar cell polarity.
  • Genetic studies in Drosophila implicated the four-jointed gene in modulating Fat signaling pathways.

Purpose of the Study:

  • To elucidate the molecular function of the four-jointed gene in Fat signaling.
  • To identify the mechanism by which Four-jointed regulates Fat and its ligand, Dachsous.

Main Methods:

  • Biochemical assays to determine the enzymatic activity of Four-jointed.
  • In vitro and in vivo experiments to assess the role of an acidic motif in Four-jointed function.
  • Localization studies to pinpoint the cellular site of Four-jointed activity.

Main Results:

  • Four-jointed encodes a protein kinase that phosphorylates serine or threonine residues on extracellular cadherin domains of Fat and Dachsous.
  • The kinase activity of Four-jointed was mapped to an acidic sequence motif (Asp-Asn-Glu).
  • Four-jointed functions within the Golgi apparatus, phosphorylating its substrates during their transit.

Conclusions:

  • Four-jointed is the first identified kinase that phosphorylates extracellular protein domains.
  • This phosphorylation by Four-jointed is a key regulatory step in Fat signaling, impacting growth and planar cell polarity.
  • The Golgi-localized phosphorylation of Fat and Dachsous by Four-jointed provides a novel mechanism for controlling cell signaling.

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