Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities

  1. Erin D Lew
  2. Jennifer Oh
  3. Patrick G Burrola
  4. Irit Lax
  5. Anna Zagórska
  6. Paqui G Través
  7. Joseph Schelssinger
  8. Greg Lemke  Is a corresponding author
  1. The Salk Institute for Biological Studies, United States
  2. Yale University School of Medicine, United States

Abstract

The TAM receptor tyrosine kinases Tyro3, Axl, and Mer regulate key features of cellular physiology, yet the differential activities of the TAM ligands Gas6 and Protein S are poorly understood. We have used biochemical and genetic analyses to delineate the rules for TAM receptor-ligand engagement, and find that the TAMs segregate into two groups based on ligand specificity, regulation by phosphatidylserine, and function. Tyro3 and Mer are activated by both ligands, but only Gas6 activates Axl. Optimal TAM signaling requires coincident TAM ligand engagement of both its receptor and the phospholipid phosphatidylserine (PtdSer): Gas6 lacking its PtdSer-binding 'Gla domain' is significantly weakened as a Tyro3/Mer agonist and is inert as an Axl agonist, even though it binds to Axl with wild-type affinity. In two settings of TAM-dependent homeostatic phagocytosis, Mer plays a predominant role while Axl is dispensable, and activation of Mer by Protein S is sufficient to drive phagocytosis.

Article and author information

Author details

  1. Erin D Lew

    The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  2. Jennifer Oh

    The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  3. Patrick G Burrola

    The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  4. Irit Lax

    Yale University School of Medicine, New Haven, CT, United States
    Competing interests
    Irit Lax, is a shareholder in Kolltan Pharmaceuticals.
  5. Anna Zagórska

    The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  6. Paqui G Través

    The Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    No competing interests declared.
  7. Joseph Schelssinger

    Yale University School of Medicine, New Haven, United States
    Competing interests
    Joseph Schelssinger, is a shareholder in Kolltan Pharmaceuticals.
  8. Greg Lemke

    The Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    lemke@salk.edu
    Competing interests
    Greg Lemke, is a shareholder in Kolltan Pharmaceuticals.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol of the Salk Institute, Animal Use Protocol No. 11-00051, approval date of record June 3, 2014.

Reviewing Editor

  1. Stephen P Goff, Howard Hughes Medical Institute, Columbia University, United States

Publication history

  1. Received: May 15, 2014
  2. Accepted: September 28, 2014
  3. Accepted Manuscript published: September 29, 2014 (version 1)
  4. Version of Record published: October 23, 2014 (version 2)

Copyright

© 2014, Lew 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. Erin D Lew
  2. Jennifer Oh
  3. Patrick G Burrola
  4. Irit Lax
  5. Anna Zagórska
  6. Paqui G Través
  7. Joseph Schelssinger
  8. Greg Lemke
(2014)
Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities
eLife 3:e03385.
https://doi.org/10.7554/eLife.03385
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