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Updated: Jan 23, 2026

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis
08:55

Characterization of MLKL-mediated Plasma Membrane Rupture in Necroptosis

Published on: August 7, 2018

11.3K

TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL

Ayaz Najafov1, Adnan K Mookhtiar1, Hoang Son Luu2

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center, Harvard Medical School, Boston, MA 02115, USA.

Molecular Cell
|June 25, 2019
PubMed

Insights

TAM kinases unexpectedly promote necroptosis, a pro-inflammatory cell death pathway. Targeting these kinases inhibits necroptosis and protects against systemic inflammation, revealing a new layer of immune regulation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Necroptosis is a pro-inflammatory cell death pathway implicated in inflammatory diseases.
  • TAM kinases (Tyro3, Axl, Mer) are known for anti-apoptotic, oncogenic, and anti-inflammatory roles.
  • The precise role of TAM kinases in necroptosis signaling remained unclear.

Purpose of the Study:

  • To investigate the role of TAM kinases in necroptosis.
  • To identify the mechanism by which TAM kinases regulate necroptosis.
  • To evaluate the therapeutic potential of targeting TAM kinases in inflammatory conditions.

Main Methods:

  • Utilized pharmacologic and genetic targeting of TAM kinases in cellular models.
  • Investigated the phosphorylation of MLKL (mixed lineage kinase-like) at Tyr376.
  • Assessed MLKL oligomerization, membranal translocation, and RIPK3-mediated phosphorylation.
  • Evaluated the effect of TAM kinase modulation on mouse models of systemic inflammatory response syndrome.

Main Results:

  • TAM kinases were identified as promoters of necroptosis.
  • Targeting TAM kinases potently inhibited necroptotic cell death.
  • Phosphorylation of MLKL Tyr376 by TAM kinases was identified as a key regulatory point.
  • TAM kinases control MLKL oligomerization, independent of RIPK3 phosphorylation or MLKL translocation.
  • Inhibition or knockout of TAM kinases protected mice from systemic inflammation.

Conclusions:

  • TAM kinases, previously known for immunosuppression, unexpectedly promote pro-inflammatory necroptosis.
  • Targeting TAM kinases offers a potential therapeutic strategy for inflammatory diseases.
  • This study elucidates the complex regulatory role of TAM kinases in inflammation and cell death pathways.
Keywords:
AxlMLKLMerTAM kinasesTyro3cell deathnecroptosis

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