A secretory kinase complex regulates extracellular protein phosphorylation

  1. Jixin Cui
  2. Junyu Xiao
  3. Vincent S Tagliabracci
  4. Jianzhong Wen
  5. Meghdad Rahdar
  6. Jack E Dixon  Is a corresponding author
  1. University of California, San Diego, United States
  2. Peking University, China
  3. Merck & Co, United States
  4. ISIS Pharmaceuticals, United States

Abstract

Although numerous extracellular phosphoproteins have been identified, the protein kinases within the secretory pathway have only recently been discovered, and their regulation is virtually unexplored. Fam20C is the physiological Golgi casein kinase, which phosphorylates many secreted proteins and is critical for proper biomineralization. Fam20A, a Fam20C paralog, is essential for enamel formation, but the biochemical function of Fam20A is unknown. Here we show that Fam20A potentiates Fam20C kinase activity and promotes the phosphorylation of enamel matrix proteins in vitro and in cells. Mechanistically, Fam20A is a pseudokinase that forms a functional complex with Fam20C, and this complex enhances extracellular protein phosphorylation within the secretory pathway. Our findings shed light on the molecular mechanism by which Fam20C and Fam20A collaborate to control enamel formation, and provide the first insight into the regulation of secretory pathway phosphorylation.

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Author details

  1. Jixin Cui

    Department of Pharmacology, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Junyu Xiao

    State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Vincent S Tagliabracci

    Department of Pharmacology, University of California, San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jianzhong Wen

    Discovery Bioanalytics, Merck & Co, Rahway, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Meghdad Rahdar

    ISIS Pharmaceuticals, Carlsbad, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jack E Dixon

    Department of Pharmacology, University of California, San Diego, San Diego, United States
    For correspondence
    jedixon@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Procedures involving mice were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the UC San Diego (Protocol #S03039).

Copyright

© 2015, Cui et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jixin Cui
  2. Junyu Xiao
  3. Vincent S Tagliabracci
  4. Jianzhong Wen
  5. Meghdad Rahdar
  6. Jack E Dixon
(2015)
A secretory kinase complex regulates extracellular protein phosphorylation
eLife 4:e06120.
https://doi.org/10.7554/eLife.06120

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https://doi.org/10.7554/eLife.06120

Further reading

    1. Biochemistry and Chemical Biology
    Saravanan Raju, Andrey S Shaw
    Insight

    The interaction between an active kinase and an ‘inactive’ pseudokinase provides clues about how these enzymes were regulated in the past, and how this regulation has evolved.